CA2380860A1 - Benzazepine derivative, production and use thereof - Google Patents

Abstract

Compounds of general formula (I) or salts thereof, which exhibit CCR5 antagonism and exert preventive and therapeutic effects against HIV infections: wherein R1 is a five- or six-membered aromatic ring which bears a substituent represented by the general formula: R-Z1-X-Z2- (wherein R is hydrogen or optionally substituted hydrocarbyl; X is optionally substituted alkylene; and Z1 and Z2 are each a heteroatom) and may be further substitute d, with R being optionally bonded to the aromatic ring to form another ring; Y is optionally substituted imino; and R2 and R3 are each optionally substituted aliphatic hydrocarbyl or an optionally substituted hetero-alicyclic group.</ SDOAB>

Description

DEMANDES OU BREVETS VOLUMINEUX
LA PRESENTE PARTIE DE CETTE DEMANDE OU CE BREVETS
COMPREND PLUS D'UN TOME.

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BENZAZEPINE DERIVATIVE, PRODUCTION AND USE THEREOF
Technical Field The present invention relates to a novel benzazepine derivative, production and use thereof.
Background Art Recently, HIV (human immunodeficiency virus) protease inhibitors are developed for method of the treatment of AIDS (acquired immunological deficient syndrome) and use of the protease inhibitors in combination with conventional two HIV reverse transcriptase inhibitors provides with a further progress of the treatment of AIDS. However, these drugs and their combination use are not sufficient for the eradications of AIDS, and development of new anti-AIDS drugs having different activity and mechanism are sought for.
As a receptor from which HIV invades to a target cell, CD4 is so far known, and recently CCRS as a second receptor of macrophage-tropic HIV and CXCR4 as a second receptor of T cell-tropic HIV, each of which is G
protein-coupled chemokine receptor having seven transmembrane domains, are respectively found out. These chemokine receptors are thought to play an essential role in establishment and spread of HIV infection. In fact, it is reported that a person who is resistant to HIV
infection in spite of several exposures retains mutation of homo deletion of CCR5 gene. Therefore, a CCR5 antagonist is expected to be a new anti-HIV drug.
However, so far, there has been no report that a CCR5 antagonist is developed as a therapeutic agent of AIDS.
Disclosure of the Invention In order to investigate an anti-AIDS drug having CCRS antagonistic activity, it is necessary to clone CCR5 gene from human tissue derived cDNA library, to ligate said gene with a vector for expression in animal cells, to introduce said gene into animal cells and to obtain cells expressing CCR5. In addition, with using this transformant, it is necessary to screen a compound which strongly inhibits binding of CC chemokine RANTES, natural ligand, to CCR5. However, so far there has been almost no report on a low molecule compound which has this CCR5 antagonistic activity and is suitable for oral administration. The present invention is to provide a novel anilide derivative which is useful for the treatment or prevention of infectious diseases of HIV and, in particular, AIDS and also which is suitable for oral administration, production and use thereof.

The present inventors diligently made extensive studies on compounds having CCR5 antagonistic activity and, as a result, they found that a benzazepine derivative of the following formula (I) or a salt thereof [hereinafter, referred to as Compound (I) in some cases]
possesses CC chemokine receptor (CCR) antagonistic activity, in particular, potent CCR5 antagonistic activity and clinically desirable pharmaceutical effect (e. g. remarkable inhibition of HIV infection to human peripheral mononuclear cells, etc.) and also that Compound (I) has superior absorbability when orally administered. Based on the finding, the present invention was accomplished.
More specifically, the present invention relates to (1) A compound of the formula (I):
V
H
i z p I ~ N~ a R
wherein R1 is a 5- to 6-membered aromatic ring which has a group of the formula: R-Z1-X-ZZ- wherein R is a hydrogen atom or an optionally substituted hydrocarbon group, X is an optionally substituted alkylene chain, and Z1 and ZZ

are respectively hetero-atoms, and which may have a further substituent, the group R may bind to the 5- to 6-membered aromatic ring to form a ring, Y is an optionally substituted imino group, R2 and R3 are respectively an optionally substituted aliphatic hydrocarbon group or an optionally substituted alicyclic heterocyclic group; or a salt thereof;
(2) A pro-drug of the compound as described in the above (1) or a salt thereof;
(3) The compound as described in the above (1), wherein the 5- to 6-membered aromatic ring is benzene, furan or thiophene;
(4) The compound as described in the above (1), wherein the 5- to 6-membered aromatic ring is benzene;

(5) The compound as described in the above (1), wherein R
is an optionally halogenated lower alkyl group (6) The compound as described in the above (1), wherein X
is - (CHz) "- (n is an integer of 1-4 ) ;

(7) The compound as described in the above (1), wherein Z1 and Zz are respectively -O-, -S(0)m- (m is an integer of 0-2) or -N(R9)- (R4 is a hydrogen atom or an optionally substituted lower alkyl group);

(8) The compound as described in the above (1), wherein Z1 is -0- or -S (0) m- (m is an integer of 0-2 ) ;

(9) The compound as described in the above (1), wherein Z1 is -0-:

(10) The compound as described in the above (1), wherein ZZ is -0- or -N (R4) - (R9 is a hydrogen atom or an optionally substituted lower alkyl group);
5 (11) The compound as described in the above (1), wherein ZZ is -0-;
(12) The compound as described in the above (1), wherein Y is -N(RS)- (R5 is a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted acyl group);
(13) The compound as described in the above (12), wherein (RS) is C1_4 alkyl, formyl or C2_5 alkanoyl;
(14) The compound as described in the above (12), wherein R5 is a group represented by the formula - (CHZ) k-Rs;
wherein k is 0 or 1, and R6 is an optionally substituted 5- to 6-membered monocyclic aromatic group;
(15) The compound as described in the above (1), wherein RZ is an optionally substituted straight chain hydrocarbon group;
(16) The compound as described in the above (1), wherein Rz is an optionally substituted lower alkyl group;
(17) The compound as described in the above (1), wherein R3 is an optionally substituted alicyclic hydrocarbon group or an optionally substituted alicyclic heterocyclic group:

(18) The compound as described in the above (17), wherein the alicyclic hydrocarbon group is a lower cycloalkyl group:
(19) The compound as described in the above (17), wherein the alicyclic hydrocarbon group is cyclohexyl:
(20) The compound as described in the above (17), wherein the alicyclic heterocyclic group is a saturated alicyclic heterocyclic group;
(21) The compound as described in the above (17), wherein the alicyclic heterocyclic group is tetrahydropyranyl, tetrahydrothiopyranyl or piperidyl;
(22) The compound as described in the above (17), wherein the alicyclic heterocyclic group is tetrahydropyranyl:
(23) The compound selected from the class consisting of 7-(4-ethoxyethoxephenyl)-1-ethyl-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carbiboxamide, 1-ethyl-7-(4-propoxyethoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide, 7-(4-butoxyethoxyphenyl)-1-ethyl-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide, 7-(4-ethoxyethoxyphenyl)-1-formyl-N-[4-[[N-methyl-N
(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1 benzazepine-4-carboxamide, 1-formyl-7-(4-propoxyethoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide, 7-(4-butoxyethoxyphenyl)-1-formyl-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide, 7-(4-butoxyethoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-5-yl)amino]methyl]phenyl]-1-propyl-2,3-dihydro-1-benzazepine-4-carboxamide, N-[4-[[N-methyl-N-(tetrahydropyran-5-yl)amino]methyl]phenyl]-7-(4-propoxyethoxyphenyl)-1-propyl-2,3-dihydro-1-benzazepine-4-carboxamide, 1-benzyl-7-(4-butoxyethoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide, 7-(4-butoxyethoxyphenyl)-1-cyclopropylmethyl-N.-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide, 7-(4-butoxyethoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1-phenyl-2,3-dihydro-1-benzazepine-4-carboxamide, 7-(4-butoxyethoxyphenyl)-1-(3,4-methylenedioxy)phenyl-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide, 7-(4-butoxyethoxyphenyl)-1-(2-methyloxazol-5-yl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide, 1-allyl-7-(4-butoxyethoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide, 7-(4-butoxyethoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1-(3-thienyl)methyl-2,3-dihydro-1-benzazepine-4-carboxamide, 7-(4-butoxyethoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1-(thiazol-2-yl)methyl-2,3-dihydro-1-benzazepine-4-carboxamide, 7-(4-butoxyethoxyphenyl)-1-(1-methylpyrazol-4-yl)methyl-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide, 7-(4-butoxyethoxyphenyl)-1-(3-methylisothiazol-4-yl)methyl-N-[4-[[N-methyl-N-(tetrahydropyran-5-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide, 7-(4-butoxyethoxyphenyl)-1-(1-ethylpyrazol-4-yl)methyl-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide, 7-(4-butoxyethoxyphenyl)-1-isobutyl-N-[4-[[N-methyl-N-(tetrahydropyran-5-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide, 1-isobutyl-N-[4-[[N-methyl-N-(tetrahydropyran-5 yl)amino]methyl]phenyl]-7-(4-propoxyethoxyphenyl)-2,3 dihydro-1-benzazepine-4-carboxamide, 7-(4-butoxyethoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1-(thiazol-5-yl)methyl-2,3-dihydro-1-benzazepine-4-carboxamide, 7-(4-butoxyethoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1-(1-methyltetrazol-5-yl)methyl-2,3-dihydro-1-benzazepine-4-carboxamide, and 7-(4-butoxyethoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1-(2-methyltetrazol-5-yl)methyl-2,3-dihydro-1-benzazepine-4-carboxamide, or salt thereof;
(24) A pro-drug of the compound as described in the above (23) or a salt thereof;
(25) A method for producing a compound of the formula:

Y
w i N Rz w 0 \~~~~Nw 3 R
wherein each symbol is as described in the above (1), or a salt thereof, which comprises subjecting a compound of 5 the formula:
Y
w - ,OH
C
n wherein each symbol is as described in the above (1), a salt or a reactive derivative thereof to a condensation reaction with a compound of the formula:
HzN w Iz NwRs wherein each symbol is as described in the above (1), or a salt thereof;
(26) A pharmaceutical composition which comprises the compound as described in the above (1) or a salt thereof;
(27) The composition as described in the above (26), which is a CC chemokine receptor (CCR) antagonist:
(28) The pharmaceutical composition as described in the above (26), which is a CCRS antagonist:
(29) The composition as described in the above (26), which is for the treatment or prevention of infectious disease of HIV;
(30) The composition as described in the above (26), which is for the treatment or prevention of AIDS;
(31) The composition as described in the above (26), which is for the prevention of the progression of AIDS;
(32) The composition as described in the above (29), which is used in combination with a protease inhibitor and/or a reverse transcriptase inhibitor;
(33) The composition as described in the above (32), wherein the reverse transcriptase inhibitor is zidovudine, didanosine, zalcitabine, lamivudine, stavudine, nevirapine, delavirdine, efavirenz or abacavir:
(34) The composition as described in the above (32), wherein the protease inhibitor is saquinavir, ritonavir, indinavir or nelfinavir;
(35) Use of the compound as described in the above (1) or a salt thereof in combination with a protease inhibitor and/or a reverse transcriptase inhibitor for the treatment or prebention of infectious diseases of HIV;
(36) A method for antagonizing a CC chemokine receptor (CCR) in a mammal, which comprises administering an effective amount of a compound described in the above (1) or a salt thereof to a mammal;
(37) Use of a compound described in the above (1) or a salt thereof in preparation of a medicament for antagonizing a CC chemokine receptor (CCR); etc.
In the above formula(I), examples of the "5- to 6-membered aromatic ring" of the "5- to 6-membered aromatic ring which has a group of the formula: R-Z1-X-Zz-wherein R is a hydrogen atom or an optionally substituted hydrocarbon group, X is an optionally substituted alkylene chain, and Z1 and Zz are respectively hetero-atoms, and which may have a further substituent"
represented by R1 include a 6-membered aromatic hydrocarbon such as benzene, etc.; 5- to 6-membered aromatic heterocyclic ring containing 1 to 4 hetero-atoms consisting of 1 to 2 kinds of hetero-atoms selected from oxygen atom, sulfur atom and nitrogen atom such as furan, thiophene, pyrrole, imidazole, pyrazole, thiazole, oxazole, isothiazole, isoxazole, tetrazole, pyridine, pyrazine, pyrimidine, pyridazine, triazole, etc.; and the like. Among others, benzene, furan, thiophene, pyridine, etc. are preferable, benzene, furan or thiophene is more preferable, and in particular, benzene is preferable.
Examples of the "hydrocarbon group" of the "optionally substituted hydrocarbon group" represented by R include (1) alkyl (e. g., C1-to alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, etc., preferably lower (C1_6) alkyl, etc., more preferable lower (C1_9) alkyl, etc,):
(2) cycloalkyl (e.g., C3_~ cycloalkyl, etc. such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.);
(3) alkenyl (e.g., CZ_lo alkenyl such as allyl, crotyl, 2-pentenyl, 3-hexenyl, etc., preferably lower (C2_6) alkenyl, etc.)~
(4) cycloalkenyl (e.g., C3_~ cycloalkenyl, etc. such as 2-cyclopentenyl, 2-cyclohexenyl, 2-cyclopentenylmethyl, 2-cyclohexenylmethyl, etc.);
(5) alkynyl,(e.g., CZ_lo alkynyl, such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-pentynyl, 3-hexynyl, etc., preferably lower (C2_6) alkynyl, etc.):
(6) aralkyl (e. g:, phenyl-C1_9 alkyl (e. g., benzyl, phenethyl, etc.), etc.):
(7) aryl (e. g., phenyl, naphthyl, etc.)~
( 8 ) cycloalkyl-alkyl (e . g. , C3_7 cycloalkyl-C1_9 alkyl such as cyclopropylmethyl, cyclobutylmethyl, cyclopentylmehyl, cyclohexylmethyl, cycloheptylmethyl, etc.), and the like.
Examples of the substituents, which the above mentioned (1) alkyl, (2) cycloalkyl, (4) cycloalkenyl, (5) alkynyl, (6) aralkyl, (7) aryl and (8) cycloalkyl-alkyl may have, include halogen (e. g., fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxy group, an optionally substituted thiol group (e. g., thiol, C1_9 alkylthio, etc.), an optionally substituted amino group (e. g. , amino; mono-C1_9 alkylamino; di-C1_4 alkylamino; 5-to 6-membered cyclic amino such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole, etc.: etc.), an optionally esterified or amidated carboxyl group (e. g., carboxyl, C1_4 alkoxy-carbonyl, carbamoyl, mono-C1_9 alkylcarbamoyl, di-C1_9 alkylcarbamoyl, etc.), an optionally halogenated C1_4 alkyl (e.g., trifluoromethyl, methyl, ethyl, etc.), an optionally halogenated C1_9 alkoxy (e. g., methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc.), C1_4 alkylenedioxy ( a . g . , -0-CHZ-0-, -0-CH2-CHZ-0, etc . ) , optionally substituted sulfonamide [e. g., a group formed by binding of an optionally substituted amino group (e. g., amino; mono-C1_9 alkylamino: di-C1_9 alkylamino; 5- to 6-membered cyclic amino such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole, etc.: etc.) to -SO2-], formyl, Cz_4 alkanoyl ( a . g . , acetyl, propionyl, etc . ) , C1_9 alkylsulfonyl (e. g., methanesulfonyl, ethanesulfonyl, etc.), etc., and the number of the substituents are 5 preferably 1 to 3.
Examples of the "heterocyclic group" of the "optionally substituted heterocyclic group" as substituents of "optionally substituted hydrocarbon group" represented by R include a group formed by 10 removing one hydrogen atom from aromatic heterocyclic ring or non-aromatic heterocyclic ring. Examples of the aromatic heterocyclic ring include 5- to 6-membered aromatic heterocyclic ring containing 1 to 4 hetero-atoms consisting of 1 to 2 kinds of hetero-atoms selected from 15 oxygen atom, sulfur atom and nitrogen atom such as furan, thiophene, pyrrole, imidazole, pyrazole, thiazole, oxazole, isothiazole, isoxazole, tetrazole, pyridine, pyrazine, pyrimidine, pyridazine, triazole, oxadiazole, thiadiazole, etc. Examples of the non-aromatic heterocycle include 5- to 6-membered non-aromatic heterocycle containing 1 to 4 hetero-atoms consisting of 1 to 2 kinds of hetero-atoms selected from nitrogen atom, sulfur atom and oxygen atom, such as tetrahydrofuran, tetrahydrothiophene, dioxolane, dithiolane, oxathiolane, pyrrolidine, pyrroline, imidazolidine, imidazoline, pyrazolidine, pyrazoline, piperidine, piperazine, oxazine, oxadiazine, thiazine, thaziadine, morpholine, thiomorpholine, pyran and tetrahydropyran, as well as non-aromatic heterocycle in which a par or whole bonds) of the aforementioned aromatic heterocycle is (are) a saturated bond, and the like (preferably, aromatic heterocycle such as pyrazole, thiazole, oxazole, tetrazole, etc.).
The "heterocyclic group" of the "optionally substituted heterocyclic group" as the substituent for the "optionally substituent hydrocarbon group"
represented by R, may have 1 to 3 substituents at an optional replaceable position. Examples of such the substituent include halogen (e. g., fluorine, chlorine, bromine and iodine), nitro, cyano, a hydroxy group, an optionally substituted thiol group (e. g., thiol, C1_4 alkylthio etc.), an optionally substituted amino group (e. g. , amino; mono-C1_4 alkyl amino; di-C1_9 alkylamino; 5-to 6-membered cyclic amino such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole, etc.: etc.), an optionally esterified or amidated carboxyl group (e. g., carboxyl, C1_4 alkoxycarbonyl, carbamoyl, mono-C1_4 alkylcarbamoyl, di-C1_ 4 alkylcarbamoyl etc.), optionally halogenated C1_4 alkyl (e. g., trifluoromethyl, methyl, ethyl, etc.), optionally halogenated C1_9 alkoxy (e. g., methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc.), C1_4 alkylenedioxy (e. g., -0-CHZ-O-, -0-CHz-CHZ-0-, etc.), optionally substituted sulfonamide [e. g., an optionally substituted amino group (e. g., amino; mono-C1_4 alkylamino; di-C1_4 alkylamino; 5- to 6-membered cyclic amino such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole, etc.~
etc. ) binding to -SOZ-] , formyl, CZ_9 alkanoyl (e. g. , acetyl, propionyl, etc.), C1_4 alkylsulfonyl (e. g., methanesulfonyl, ethanesulfonyl, etc.), etc. (preferably, C1_4 alkyl, etc. ) .
When the group of the formula: R-Z1-X-Z2- wherein each symbol is as defined above is a monovalent group, that is, it does not bind to the 5- to 6-membered aromatic ring to form a ring, as the group R, an optionally substituted alkyl group is preferable, an optionally halogenated lower alkyl group is more preferable, and in particular, an optionally halogenated C1_4 alkyl group is preferable.
Examples of the "optionally substituted alkylene chain" represented by X include an optionally substituted straight or branched C1_6 alkylene, etc. In said alkylene chain, a straight portion is preferably constituted by 1-4 carbon atoms, and in particular, an optionally substituted straight C1_9 alkylene (preferably ethylene or propylene) is preferable as X.
Examples of the substituent, which the "alkylene chain" of the "optionally substituted alkylene chain"
represented by X may have, include any one which can bind to a divalent chain constituting the straight portion, for example, C1_6 lower alkyl (e. g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, etc.), lower (C3_7) cycloalkyl (e. g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.), formyl, lower (C2_7) alkanoyl (e.g., acetyl, propionyl, butyryl, etc.), an optionally esterified phosphono group, an optionally esterified carboxyl group, hydroxy group, oxo, etc., and more preferably C1_6 lower alkyl (preferably C1_3 alkyl) , hydroxy group, oxo, etc.
Examples of the optionally esterified phosphono group include a group of the formula: P (O) (OR') (0R8) wherein R' and Re are independently hydrogen, a C1_6 alkyl group or a C3_~ cycloalkyl group, and R' and R8 may bind to each other to form a 5- to 7-membered ring.
In the above formula, examples of the C1_6 alkyl group represented by R' and Re include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, etc., and examples of the C3_, cycloalkyl include cyclopropyl. cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. Among others, a straight C1_6 lower alkyl is preferable and C1_3 lower alkyl is more preferable. The groups R' and Re may be the same or different, and preferably the groups R' and R8 are the same. When R' and Re may bind to each other to form a 5- to 7-membered ring, the groups R' and R8 bind to each other to represent a straight CZ_9 alkylene chain of the formula: - (CH2) 2-, - (CHZ) 3-, - (CHz) Q-, etc. Said chain may have a substituent, and examples of the substituent include hydroxy group, halogen, etc.
Examples of the optionally esterified carboxyl group include a carboxyl group and an ester group formed by binding a carboxyl group to a C1_6 alkyl group or a C3_, cycloalkyl group (e. g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isoprpoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxy-carbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc.).
As the group X, an optionally substituted C1_4 alkylene is preferable, C1_9 alkylene which may be substituted with C1_3 alkyl, hydroxy group or oxo is more preferable, and in particular, a group of the formula: -(CHZ)n- (n is an integer of 1-4) is preferable.
Examples of the hetero-atom represented by Z1 and Z2 include -0-, -S (0)m- (m is an integer of 0-2 ) , -N (R4) - (R9 is a hydrogen atom or an optionally substituted lower alkyl group), etc. As the group Z1, -0- or -S(0)m- (m is an integer of 0-2) is preferable, and -O- is more preferable. As the group Zz, -0- or -N (R9) - (R4 is a 5 hydrogen atom or an optionally substituted lower alkyl group) is preferable, and -0- is more preferable.
Examples of the "optionally substituted lower alkyl group" represented by R9 include the same as the above "optionally substituted lower alkyl group" exemplified 10 with respect to the "optionally substituted hydrocarbon group" represented by R.
Examples of the further substituent, which the "5-to 6-membered ring" of the "5- to 6-membered aromatic ring which has a group of the formula: R-Z1-X-ZZ- wherein 15 each symbol is as defined above, and which may have a further substituent" represented by R1 may have, in addition to the group of the formula: R-Z1-X-ZZ-, include a halogen atom, nitro, cyano, an optionally substituted alkyl, an optionally substituted cycloalkyl, an 20 optionally substituted hydroxy group, an optionally substituted thiol group (wherein a sulfur atom may be oxidized to form an optionally substituted sulfinyl group or an optionally substituted sulfonyl group), an optionally substituted amino group, an optionally substituted acyl group, an optionally esterified or amidated carboxyl group, an optionally substituted aromatic group and the like.
Examples of the halogen as the substituents for R1 include fluorine, chlorine, bromine, iodine, etc. Among others, fluorine and chlorine are preferable.
Examples of the alkyl in the optionally substituted alkyl as the substituents for R1 include a straight or branched C1_lo alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, etc., and preferably lower (C1_6) alkyl. Examples of the substituents in the optionally substituted alkyl include halogen (e. g., fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxy group, an optionally substituted thiol group (e.g., thiol, Cl_9 alkylthio, etc.), an optionally substituted amino group (e. g., amino; mono-Cl_4 alkylamino: di-C1_9 alkylamino~ 5-to 6-membered cyclic amino such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole, etc.;
etc.), an optionally esterified or amidated carboxyl group (e. g., carboxyl, C1_4 alkoxy-carbonyl, carbamoyl, mono-C1_9 alkylcarbamoyl, di-C1_9 alkylcarbamoyl, etc. ) , an optionally halogenated C1_9 alkoxy (e. g., methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc.), an optionally halogenated C1_9 alkoxy-C1_9 alkoxy (e.g., methoxymethoxy, methoxyethoxy, ethoxyethoxy, trifluoromethoxyethoxy, trifluoroethoxyethoxy, etc.), formyl, Cz_9 alkanoyl (e.g. acetyl, propionyl, etc.), C1-4 alkylsuflonyl (e. g., methanesulfonyl, ethanesulfonyl, etc.), etc., and the number of the substituents are preferable 1 to 3.
Examples of the cycloalkyl in the optionally substituted cycloalkyl as the substituents for R1 include C3_, cycloalkyl, etc. such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. Examples of the substituents in the optionally substituted cycloalkyl include halogen (e. g., fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxy group, an optionally substituted thiol group (e. g., thiol, C1_9 alkylthio, etc.), an optionally substituted amino group (e. g., amino, mono-C1_9 alkylamino; di-C1_4 alkylamino; 5- to 6-membered cyclic amino such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole, etc.: etc.), an optionally esterified or amidated carboxyl group (e. g., carboxyl, C1_9 alkoxy-carbonyl, carbamoyl, mono-C1_4 alkylcarbamoyl, di-C1_9 alkylcarbamoyl, etc.), an optionally halogenated C1_4 alkyl (e.g., trifluoromethyl, methyl, ethyl, etc.), an optionally halogenated C1_4 alkoxy (e. g., methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc.), formyl, CZ_4 alkanoyl ( a . g . , acetyl, propionyl, etc . ) , C1_4 alkylsulfonyl (e. g. methanesulfonyl, ethanesulfonyl, etc.), etc., and the number of the substituents are preferably 1 to 3.
Examples of the substituents in the optionally substituted hydroxy group as the substituents for R1 include (1) an optionally substituted alkyl (e. g., C1_lo alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, etc., preferably lower (C1_6) alkyl, etc. ) ;
(2) an optionally substituted cycloalkyl which may contain a hetero-atom (e.g., C3_, cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.; a saturated 5- to 6-membered heterocyclic ring group containing 1-2 hetero-atoms such as tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, pyrazolidinyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrothiopyranyl, etc.; etc., (preferably, tetrahydropyranyl, etc.));
(3) an optionally substituted alkenyl (e. g., Cz_to alkenyl such as allyl, crotyl, 2-pentenyl, 3-hexenyl, etc., preferably lower (C2_6) alkenyl, etc.);
(4) an optionally substituted cycloalkenyl (e. g. C3_~

cycloalkenyl, etc. such as 2-cyclopentenyl, 2-cyclohexenyl, 2-cyclopentenylmethyl, 2-cyclohexenylmethyl, etc.);
(5) an optionally substituted aralkyl (e. g. phenyl-C1_4 alkyl (e. g. benzyl, phenethyl, etc.), etc.);
(6) formyl or an optionally substituted acyl (e. g. C2_4 alkanoyl(e.g. acetyl, propionyl, butyryl, isobutyryl, etc.), C1_4 alkylsulfonyl (e. g. methanesulfonyl, ethanesulfonyl, etc.), etc.);
(7) an optionally substituted aryl (e. g. phenyl, naphthyl, etc.); etc.
Examples of the substituents which the above-mentioned (1) optionally substituted alkyl, (2) optionally substituted cycloalkyl, (3) optionally substituted alkenyl, (4) optionally substituted cycloalkenyl, (5) optionally substituted aralkyl, (6) optionally substituted acyl and (7) optionally substituted aryl may have include halogen (e. g., fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxy group, an optionally substituted thiol group (e. g., thiol, C1_4 alkylthio, etc.), an optionally substituted amino group (e.g. amino; mono-C1_4 alkyl amino; di-C1_4 alkylamino; 5- to 6-membered cyclic amino such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole, etc.; etc.), an optionally esterified or amidated carboxyl group (e. g., carboxyl, C1_4 alkoxy-carbonyl, carbamoyl, mono-C1_9 alkylcarbamoyl, di-C1_9 alkylcarbamoyl, etc.), an optionally halogenated C1_9 alkyl (e. g., trifluoromethyl, 5 methyl, ethyl, etc.), an optionally halogenated C1_s alkoxy (e. g., trifluoromethoxy, trifluoroethoxy, etc.;
preferably an optionally halogenated C1_4 alkoxy), formyl, Cz_4 alkanoyl (e. g. , acetyl, propionyl, etc. ) , C1_9 alkoxy) , C1_9 alkylsulfonyl (e. g., methanesulfonyl, ethanesulfonyl, 10 etc.), an optionally substituted 5- to 6-membered aromatic heterocyclic ring [e. g., 5- to 6-membered aromatic heterocyclic ring containing 1 to 4 hetero-atoms consisting of 1 to 2 kinds of hetero-atoms selected from oxygen atom, sulfur atom and nitrogen atom such as furan, 15 thiophene, pyrrole, imidazole, pyrazole, thiazole, oxazole, isothiazole, isoxazole, tetrazole, pyridine, pyrazine, pyrimidine, pyridazine, triazole, etc.;
examples of the substituents which said heterocyclic ring may have include halogen (e. g., fluorine, chlorine, 20 bromine, iodine, etc.), nitro, cyano, hydroxy group, thiol group, amino group, carboxyl group, an optionally halogenated C1_9 alkyl (e. g., trifluoromethyl, methyl, ethyl, etc.), an optionally halogenated C1_4 alkoxy (e. g., methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, 25 trifluoroethoxy, etc.), formyl, CZ_4 alkanoyl (e. g., acetyl, propionyl, etc.), C1_4 alkylsulfonyl (e. g., methanesulfonyl, ethanesulfonyl, etc.), etc.; and the number of the substituents are preferable 1 to 3.], etc., and the number of the substituents are preferably 1 to 3.
Examples of the substituents in the optionally substituted thiol group as the substituents for R1 are the same as the above-described substituents of the optionally substituted hydroxy group as the substituents for R1, and among others, (1) an optionally substituted alkyl (e. g., C1_lo alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, etc. preferably lower (C1_6) alkyl, etc. ) ;
(2) an optionally substituted cycloalkyl (e. g., C3_, cycloalkyl, etc. such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.);
(3) an optionally substituted aralkyl (e. g., phenyl-C1_4 alkyl (e. g. benzyl, phenethyl, etc.), etc.);
(4) an optionally substituted aryl (e. g., phenyl, naphthyl, etc.); etc. are preferable.
Examples of the substituents which the above-mentioned (1) optionally substituted alkyl, (2) optionally substituted cycloalkyl, (3) optionally substituted aralkyl and (4) optionally substituted aryl may have include halogen (e. g., fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxy group, an optionally substituted thiol group (e. g., thio, C1_4 alkylthio, etc.), an optionally substituted amino group (e.g., amino; mono-C1_9 alkylamino: di-C1_4 alkylamino; 5-to 6-membered cyclic amino such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole, etc.; etc.), an optionally esterified or amidated carboxyl group (e. g., carboxyl, C1_4 alkoxy-carbonyl, carbamoyl, mono-C1_4 alkylcarbamoyl, di-C1_4 alkylcarbamoyl, etc.), an optionally halogenated C1_9 alkyl (e.g., trifluoromethyl, methyl, ethyl, etc.), an optionally halogenated C1_9 alkoxy (e. g., methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc.), formyl, Cz_9 alkanoyl (e. g., acetyl, propionyl, etc.), C1_4 alkylsulfonyl (e. g., methanesulfonyl, ethanesulfonyl, etc.), etc., and the number of the substituents are preferably 1 to 3.
Examples of the substituents of the optionally substituted amino group as the substituents for R1 include an amino group which may have the same one to two substituents as those of the above-described substituents of "the optionally substituted hydroxy group as the substituents for R1", etc. Among others, (1) an optionally substituted alkyl (e. g., C1-to alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, etc., preferably lower (C1_6) alkyl, etc. ) ;
(2) an optionally substituted cycloalkyl (e. g., C3_~
cycloalkyl, etc. such as cyclopropyl, cyclobutyl cyclopentyl, cyclohexyl, cycloheptyl, etc.):
(3) an optionally substituted alkenyl (e. g., CZ_lo alkenyl such as allyl, crotyl, 2-pentenyl, 3-hexenyl, etc., preferably lower (C2_6) alkenyl, etc.):
(4) an optionally substituted cycloalkenyl (e. g., C3_~
cycloalkenyl, etc. such as 2-cyclopentenyl, 2-cyclohexenyl, 2-cyclopentenylmethyl, 2-cyclohexenylmethyl, etc.):
(5) formyl or an optionally substituted acyl (e. g., CZ_4 alkanoyl (e. g., acetyl, propionyl, butyryl, isobutyryl, etc.), C1_9 alkylsulfonyl (e. g., methanesulfonyl, ethanesulfonyl, etc.), etc.):
(6) an optionally substituted aryl (e. g., phenyl, naphthyl, etc.); etc. are preferable.
Examples of the substituents, which each of the above-described (1) optionally substituted alkyl, (2) optionally substituted cycloalkyl, (3) optionally substituted alkenyl, (4) optionally substituted cycloalkyl,(5) optionally substituted acyl and (6) optionally substituted aryl may have, include halogen (e. g., fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxy group, an optionally substituted thiol group (e. g., thiol, Cl_4 alkylthio, etc.), an optionally substituted amino group (e. g., amino; mono-C1_9 alkylamino; di-C1_9 alkylamino~ 5-to 6-membered cyclic amino such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole, etc.;
etc.), an optionally esterified or amidated carboxyl group (e. g., carboxyl, C1_9 alkoxy-carbonyl, carbamoyl, mono-C1_14 alkylcarbamoyl, di-C1_9 alkylcarbamoyl, etc. ) , an optionally halogenated C1_4 alkyl (e. g., trifluoromethyl, methyl, ethyl, etc.), an optionally halogenated C1_4 alkoxy (e. g., methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc.), formyl, CZ_4 alkanoyl (e. g., acetyl, propionyl, etc.), C1_4 alkylsulfonyl (e. g., methanesulfonyl, ethanesulfonyl, etc.), etc., and the number of the substituents are preferably 1 to 3.
The substituents in the optionally substituted amino group as the substituents for R1 may bind to each other to form a cyclic amino group (e. g., 5- to 6-membered cyclic amino, etc. such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole, etc.). Said cyclic amino group may have a substituent and examples of the substituents include halogen (e. g., fluorine, chlorine, bromine, iodine, etc.), nitro cyano, hydroxy group, an optionally substituted 5 thiol group (e.g., thiol, C1_4 alkylthio, etc.), an optionally substituted amino group (e. g., amino; mono-C1_4 alkylamino: di-C1_9 alkylamino; 5-to 6-membered cyclic amino such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole, etc.;
10 etc.), an optionally esterified or amidated carboxyl group (e. g., carboxyl, C1_4 alkoxy-carbonyl, carbamoyl, mono-C1_9 alkylcarbamoyl, di-C1_9 alkylcarbamoyl, etc. ) , an optionally halogenated C1_9 alkyl (e. g., trifluoromethyl, methyl, ethyl, etc.), an optionally halogenated C1_4 15 alkoxy (e. g., methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc.), formyl, CZ_4 alkanoyl (e. g., acetyl, propionyl, etc.), C1_9 alkylsulfonyl (e. g., methanesulfonyl, ethanesulfonyl, etc.), etc., and the number of the substituents are 20 preferably 1 to 3.
Examples of the optionally substituted acyl as the substituents for R1 include (1) hydrogen;
(2) an optionally substituted alkyl (e. g., C1_lo alkyl such 25 as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, octyl, nonyl, decyl, etc., preferably lower (C1_6) alkyl, etc.):
(3) an optionally substituted cycloalkyl (e.g., C3-~
cycloalkyl, etc. such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.);
(4) an optionally substituted alkenyl (e. g., Cz_lo alkenyl such as allyl, crotyl, 2-pentenyl, 3-hexenyl, etc., preferably lower (C2_6) alkenyl, etc.);
(5) an optionally substituted cycloalkenyl (e. g., C3_~
cycloalkenyl, etc. such as 2-cyclopentenyl, 2-cyclohexenyl, 2-cyclopentenylmethyl, 2-cyclohexenylmethyl, etc.):
(6) an optionally substituted 5-to 6-membered monocyclic aromatic group (e. g., phenyl, 5- to 6-membered aromatic heterocyclic group (e. g., 5- to 6-membered aromatic heterocyclic group containing 1 to 4 hetero-atoms consisting of 1 to 2 kinds of hetero-atoms selected from oxygen atom, sulfur atom and nitrogen atom, such as furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, tetrazolyl, pyridyl, pyrazyl, pirimidinyl, pyridazinyl, triazolyl, etc.);
(7) an optionally substituted 5- to 6-membered monocyclic non-aromatic heterocyclic group (e.g., a group which is formed by removing one hydrogen atom from a 5- to 6-membered monocyclic non-aromatic heterocycle containing 1 to 4 hetero-atoms consisting of 1 to 2 kinds of hetero-atoms selected from nitrogen atom, sulfur atom and nitrogen atom, such as tetrahydrofuran, tetrahydrothiophene, dioxolane, dithiolane, oxathiolane, pyrrolidine, pyrroline, imidazolidine, imidazoline, pyrazolidine, pyrazoline, piperidine, piperazine, oxazine, oxadiazine, thiazine, thiadiazine, morpholine, thiomorpholine, pyran, tetrahydropyran, etc.; preferably dioxolanyl, etc) which is bound to a carbonyl group or a sulfonyl group (e. g., acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, butanoyl, octanoyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cyclobutanecarbonyl, crotonyl, 2-cycohexenecarbonyl, benzoyl, nicotinyl, methanesulfonyl, ethanesulfonyl, etc.). Examples of the substituents, which the above-mentioned (2) optionally substituted alkyl, (3) optionally substituted cycloalkyl, (4) optionally substituted alkenyl, (5) optionally substituted cycloalkenyl, (6) optionally substituted 5- to 6-membered monocyclic aromatic group and (7) optionally substituted 5- to 6-membered monocyclic non-aromatic heterocycle may have, include halogen (e. g., fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxy group, an optionally substituted thiol group (e. g., thiol, C1_4 alkylthio, etc.), an optionally substituted amino group (e. g., amino; meno-C1_9 alkylamino; di-C1_4 alkylamino; 5- to 6-membered cyclic amino such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole, etc.; etc.), an optionally esterified or amidated carboxyl group (e. g., carboxyl, C1_4 alkoxy-carbonyl, carbamoyl, mono-C1_4 alkylcarbamoyl, di-C1_4 alkylcarbamoyl, etc.), an optionally halogenated C1_4 alkyl (e.g., trifluoromethyl, methyl, ethyl, etc.), an optionally halogenated C1_4 alkoxy (e. g., methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc.), C1_9 alkylenedioxy (e.g., -0-CHZ-0-, -O-CHZ-CHZ-O-, etc.), optionally substituted sulfonamide [e. g., an optionally substituted amino group (e. g. amino: mono-C1_9 alkylamino;
di-C1_4 alkylamino; 5- to 6-membered cyclic amino such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole, etc.) which is bound to -SOZ-, etc. ] , formyl, CZ_9 alkanoyl (e. g. , acetyl, propionyl, etc.), C1_9 alkylsulfonyl (e. g., methanesulfonyl, ethanesulfonyl, etc.), etc., and the number of the substituents are preferably 1 to 3.
Examples of the optionally esterified carboxyl group as the substituents for R1 include (1) hydrogen;

(2) an optionally substituted alkyl (e. g., C1_lo alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, etc., preferably lower (C1_6) alkyl, etc. ) ;
(3) an optionally substituted cycloalkyl (e. g., C3_, cycloalkyl, etc. such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.);
(4) an optionally substituted alkenyl (e. g., CZ_lo alkenyl such as allyl, crotyl, 2-pentenyl, 3-hexenyl, etc., preferably lower (C2_6) alkenyl, etc.);
(5) an optionally substituted cycloalkenyl (e. g., C3_~
cycloalkenyl, etc. such as 2-cyclopentenyl, 2-cyclohexenyl, 2-cyclopentenylmethyl, 2-cyclohexenylmethyl, etc.):
(6) an optionally substituted aryl (e. g., phenyl, naphthyl, etc.); etc., and preferably carboxyl, lower (C1_ 6) alkoxycarbonyl, aryloxycarbonyl (e. g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, phenoxycarbonyl, naphthoxycarbonyl, etc.), etc.
Examples of the substituents, which the above-mentioned (2) optionally substituted alkyl, (3) optionally substituted cycloalkyl, (4) optionally substituted alkenyl, (5) optionally substituted cycloalkenyl and (6) optionally substituted aryl may have, include halogen (e. g., fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxy group, an optionally substituted thiol group (e. g., thiol, C1_9 alkylthio, etc.), an optionally substituted amino group (e. g., 5 amino; mono-C1_9 alkylamino; di-C1_9 alkylamino; 5- to 6-membered cyclic amino such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole, etc.; etc.), an optionally esterified or amidated carboxyl group (e. g., carboxyl, C1_4 alkoxy-10 carbonyl, carbamoyl, mono-C1_4 alkylcarbamoyl, di-C1_4 alkylcarbamoyl, etc.), an optionally halogenated C1_9 alkyl (e.g., trifluoromethyl, methyl, ethyl, etc.), an optionally halogenated C1_4 alkoxy (e. g., methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc.), 15 formyl, CZ_4 alkanoyl (e.g., acetyl, propionyl, etc.), C1_9 alkylsulfonyl (e. g., methanesulfonyl, ethanesulfonyl, etc.), etc., and the number of the substitutes are preferably 1 to 3.
Examples of the optionally amidated carboxyl group 20 as the substitutes for R1 include an carbonyl group binding to "an optionally substituted amino group" , etc.
which is the same as that of the above-described "optionally substituted amino group as the substituents for R1" , and among others, carbamoyl, mono-C1_s 25 alkylcarbamoyl, di-C1_6 alkylcarbamoyl, etc. are preferable.
Examples of the aromatic group in the optionally substituted aromatic group as the substituents for R1 include 5- to 6-membered aromatic homocyclic or heterocyclic ring such as phenyl, pyridyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, tetrazolyl, pyrazinyl pyrimidinyl, pyridazinyl, triazolyl, oxadiazolyl, thiadiazolyl, etc.; fused aromatic heterocyclic ring such as benzofuran, indole, benzothiophene, benzoxazole, benzothiazole, indazole, benzimidazole, quinoline, isoquinoline, quinoxaline, phthalazine, quinazoline, cinnoline, etc.; etc. Examples of the substituents for these aromatic groups include halogen (e. g., fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxy group, an optionally substituted thiol group (e. g., thiol, C1_Q alkylthio, etc.), an optionally substituted amino group (e. g. , amino; mono-C1_4 alkylamino; di-C1_4 alkylamino; 5- to 6-membered cyclic amino such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole, etc.; etc.), an optionally esterified or amidated carboxyl group (e. g., carboxyl, C1_4 alkoxy-carbonyl, carbamoyl, mono-C1_4 alkylcarbamoyl, di-C1_9 alkylcarbamoyl, etc.), an optionally halogenated C1_9 alkyl (e. g., trifluoromethyl, methyl, ethyl, etc.), an optionally halogenated C1_4 alkoxy (e. g., methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc.), formyl, Cz_4 alkanoyl (e. g., acetyl, propionyl, etc.), C1_9 alkylsulfonyl (e. g., methanesulfonyl, ethanesulfonyl, etc.), etc., and the number of the substituents are preferably 1 to 3.
The number of the above-mentioned substituents for R1 is 1-4 (preferably 1-2) and they may be the same or different and present at any possible position on the ring represented by R1.
When the group represented by R binds to the 5- to 6-membered aromatic ring to form a ring, the group of the formula: R-Z1-X-ZZ- wherein each symbol is as defined above (as the group R is preferably hydrogen atom) forms a divalent group such as lower (C1_6) alkylenedioxy (e. g., -0-CHz-0-, -0-CHZ-CH2-0-, -0-CHZ-CHZ-CHZ-0-, etc. ) , oxy-lower (C1_6) alkylene-amino (e. g. , -0-CHZ-NH-, -0-CHZ-CHZ-NH-, etc.), oxy-lower (C1_6) alkylenethio (e.g., -0-CHz-S-, -0-CHz-CHz-S-, etc. ) , lower {C1_6) alkylenediamino (e.g., -NH-CH2-NH-, -NH-CHZ-CHZ-NH-, etc. ) , thia-lower (C1_6) alkylene-amino (e. g., -S-CHz-NH-, -S-CHZ-CHZ-NH-, etc.), etc.
Preferred examples of the further substituent, which the "5- to 6-membered ring" of the "5- to 6-membered aromatic ring which has a group of the formula: R-Zl-X-ZZ-wherein each symbol is as defined above, and which may have a further substituent" represented by R1 may have, in addition to the group of the formula: R-Z1-X-ZZ-, include, in particular, a lower (C1_4) alkyl optionally substituted with a halogen or a lower (C1_4) alkoxy (e. g., methyl, ethyl, t-butyl, trifluoromethyl, methoxymethyl, ethoxymethyl, propoxymethyl, butoxymethyl, methoxyethyl, ethoxyethoxy, propoxyethyl, butoxyethyl, etc.), a lower (C1-4) alkoxy optionally substituted with a halogen or a lower (C1_9) alkoxy (e. g., methoxy, ethoxy, propoxy, butoxy, t-butoxy, trifluoromethoxy, methoxymethoxy, ethoxymethoxy, propoxymethoxy, butoxymethoxy, methoxyethoxy, ethoxyethoxy, propoxyethoxy, butoxyethoxy, methoxypropoxy, ethoxypropoxy, propoxypropoxy, butoxypropoxy, etc.), halogen (e. g., fluorine, chlorine, etc.), nitro, cyano, an amino group optionally substituted with 1-2 lower (C1_9) alkyl groups, formyl group or lower (C2_9) alkanoyl groups (e. g., amino, methylamino, dimethylamino, fromylamino, acethylamino, etc.), 5- to 6-membered cyclic amino (e.g., 1-pyrrolidinyl, 1-piperazinyl, 1-piperidinyl, 4-morpholino, 4-thiomorpholino, 1-imidazolyl, 4-tetrahydropyranyl, etc.), etc.
When R1 is a benzene, the "group of the formula: R-Z1-X-ZZ-" is preferably present at para position and the further substituent, which the "5- to 6-membered aromatic ring which may have, in addition to the group of the formula: R-Z1-X-ZZ- is preferably present at meta position.
In the above formula, examples of the "optionally substituted imino group" represent by Y include a divalent group of the formula: -N(RS)- wherein RS is hydrogen atom or a substituent, etc.
As R5, hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted hydroxy group, an optionally substituted thiol group (the sulfur atom may be oxidized to form an optionally substituted sulfinyl group or an optionally substituted sulfonyl group), an optionally substituted amino group, an optionally esterified or amidated carboxyl group, and an optionally substituted acyl group, etc. are preferable, and hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group and an optionally substituted acyl group, etc. are more preferable.
As the preferable R5, hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted acyl group, etc. are preferable, C1_9 alkyl, C1_9 alkylsulfonyl, formyl, Cz_5 alkanoyl etc. are more preferable, C1_9 alkyl, formyl, Cz_5 alkanoyl etc. are further more preferable, and in particular, formyl or ethyl is preferable. As other preferably R5, there is a 5 group represented by the formula -(CHZ)k-R6 [wherein k represents 0 or 1, R6 represents an optionally substituted 5- to 6-membered monocyclic aromatic group (similar to "(6) an optionally substituted 5- to 6-membered monocyclic aromatic group" exemplified with 10 respect to an optionally substituted acyl group as the substituent for R1; preferably phenyl, pyrazolyl, thiazolyl, oxazolyl, tetrazolyl, etc., each being optionally substituent with halogen, optionally halogenated C1_9 alkyl, optionally halogenated C1_4 alkoxy, 15 etc.)].
Example of the "optionally substituted hydrocarbon group" as R5 are the same as the "optionally substituted hydrocarbon group" of R. Examples of the "optionally substituted heterocyclic group" as RS include the same 20 "optionally substituted heterocyclic group" as the substituent for the "optionally substituted hydrocarbon group" represented by R, and examples of the "optionally substituted hydroxy group" , the "optionally substituted thiol group" , the "optionally substituted amino group" , 25 the "optionally esterified or amidated carboxyl group"

and the "optionally substituted acyl group" as RS include the same "optionally substituted hydroxy group" , "optionally substituted thiol group" , "optionally substituted amino group" , "optionally esterified or amidated carboxyl group" and "optionally substituted acyl group" as the substituent for R1.
In the above formula (I), examples of the "optionally substituted aliphatic hydrocarbon group"
(aliphatic straight chain hydrocarbon group and aliphatic cyclic hydrocarbon group) represented by R2 and R3 include (1) an optionally substituted alkyl (e. g., C1_lo alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, etc., preferably lower (C1_6) alkyl, etc. ) (2) an optionally substituted cycloalkyl (e. g., C3_e cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc.; etc.), provided that (2-1) said cycloalkyl may contain one hetero-atom selected from a sulfur atom, an oxygen atom and a nitrogen atom to form oxirane, thiorane, aziridine, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, tetrahydropyran, tetrahydrothiopyran, tetrahydrothiopyran 1-oxide, piperidine, etc. (preferably, 6-membered ring such as tetrahydropyran, tetrahydrothiopyran, piperidine, etc.); that (2-2) said cycloalkyl may be fused with a benzene ring to form indane, tetrahydronaphthalene, etc. (preferably, indane, etc.): and that (2-3) said cycloalkyl may have a bridging through a straight chain constituted by 1-2 carbon atoms to form a bridged hydrocarbon residue such as bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, etc., preferably, a cyclohexyl group, etc. having a bridging through a straight chain constituted by 1-2 carbon atoms, and more preferably bicycle[2.2.1]heptyl, etc.:
(3) an optionally substituted alkenyl (e. g., Cz_lo alkenyl such as allyl, crotyl, 2-pentenyl, 3-hexenyl etc., preferably lower (Cz_6)alkenyl, etc.);
(4) an optionally substituted cycloalkenyl (e. g., C3_, cycloalkenyl, etc. such as 2-cyclopentenyl, 2-cyclohexenyl, 2-cyclopentenylmethyl, 2-cyclohexenylmethyl, etc.): etc.
Examples of the substituents, which the above-mentioned (1) optionally substituted alkyl, (2) optionally substituted cycloalkyl, (3) optionally substituted alkenyl and (4) optionally substituted cycloalkenyl may have, include halogen (e. g., fluorine, chlorine, bromine, iodine, etc.), an optionally halogenated lower (C1_9)alkyl, an optionally halogenated lower C1_4 alkoxy (e. g., methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc.), C1_4 alkylenedioxy (e. g., -0-CHZ-0-, -0-CHZ-GHZ-0-, etc.), formyl, CZ_4 alkanoyl (e. g., acetyl, propionyl, etc.), C1_9 alkylsulfonyl (e. g., methanesulfonyl, ethanesulfonyl, etc. ) , phenyl-lower (C1_9) alkyl, C3_~ cycloalkyl, cyano, nitro, hydroxy group, an optionally substituted thiol group (e. g., thiol, C1_4 alkylthio, etc.), an optionally substituted amino group (e. g., amino mono-C1_4 alkylamino; di-C1_4 alkylamino; 5- to 6-membered cyclic amino such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole, etc.;
etc.), an optionally esterified or amidated carboxyl group (e. g., carboxyl, C1_4 alkoxy-carbonyl, carbamoyl, mono-C1_4alkylcarbamoyl, di-C1_4 alkylcarbamoyl, etc. ) , a lower (C1_9) alkoxy-carbamoyl, oxo group (preferably, halogen, an optionally halogenated lower (C1_4) alkyl, an optionally halogenated lower (C1_9) alkoxy, phenyl-lower (C1_4) alkyl, C3_~ cycloalkyl, cyano, hydroxy group, etc. ) , etc., and the number of the substituents are preferably 1 to 3.
Preferred examples of the "optionally substituted aliphatic hydrocarbon group" represented by RZ and R3 include (1) a lower (C1_6) straight or branched alkyl which may have 1-3 substituents selected from the class consisting of halogen, cyano, hydroxy group and C3_, cycloalkyl;
(2) CS_e cycloalkyl which may be substituted with 1-3 substituents selected from the class consisting of a halogen, an optionally halogenated lower (C1_9) alkyl and a phenyl-lower (C1_4) alkyl, which may contain a hetero-atom selected from the class consisting of a sulfur atom, an oxygen atom and a nitrogen atom, which may be fused with a benzene ring and which may have a bridging through a C1_2 straight chain (e. g., cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, tetrahydropyranyl, tetrahydrothiapyranyl, piperidinyl, indanyl, tetrahydronaphthalenyl, piperidinyl, indanyl, tetrahydronaphthalenyl, bicyclo[2.2.1]heptyl, etc., each of which may be substituted);etc.
In the above formula (I), example of the "optionally substituted alicyclic (non-aromatic) heterocyclic group" represented by RZ and R3 include 5-to 6-membered non-aromatic heterocyclic ring containing 1 to 4 hetero-atoms consisting of 1 to 2 kinds of hetero-atoms selected from oxtgen atom, sulfur atom and nitrogen atom such as tetrahydrofuran, tetrahydrothiophene, dioxolane, dithiolane, oxathiolane, pyrrolidine, pyrroline, imidazolidine, imidazoline, pyrazolidine, pyrazoline, piperidine, piperazine, oxazine, oxadiazine, thiazine, thiadiazine, morpholine, thiomorpholine, pyran, tetrahydropyran etc. Among others, a 5- to 6-membered 5 non-aromatic heterocyclic ring containing 1 hetero-atom such as tetrahydrofuran, piperidine, tetrahydropyran, tetrahydrothiopyran, etc. and so on are preferable.
Examples of the substituent, which the "alicylic heterocyclic group" in the "optionally substituted 10 alicyclic heterocyclic group" represented by Rz and R3 may have, include halogen (e. g., fluorine, chlorine, bromine, iodine, etc.), an optionally halogenated lower (C1_4) alkyl, an optionally halogenated C1_9 alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, 15 trifluoroethoxy, etc.), C1_9alkylenedioxy (e.g., -0-CHZ-0-, -0-CHZ-CHz-0-, etc.), formyl, Cz_9alkanoyl (e.g., acetyl, propionyl, etc.), C1_4alkylsulfonyl (e. g., methanesulfonyl, ethanesulfonyl, etc. ) , phenyl-lower (C1_4) alkyl, C3_, cycloalkyl, cyano, nitro, hydroxy group, an optionally 20 substituted thiol group (e. g., thiol, C1_4 alkylthio, etc.), an optionally substituted amino group (e. g. amino;
mono-C1_9 alkylamino; di-C1_4alkylamino; 5- to 6-membered cyclic amino such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, 25 imidazole, etc.; etc.), an optionally esterified or , CA 02380860 2001-12-03 amidated carboxyl group (e. g., carboxyl, C1_9alkoxy-carbonyl, carbamoyl, mono-C1_4alkylcarbamoyl, di-C1_4 alkylcarbamoyl, etc.), a lower (C1_9) alkoxy-carbonyl, oxo group (preferably, halogen, an optionally halogenated lower (C1_4) alkyl, an optionally halogenated lower (C1_9) alkoxy, phenyl-lower (C1_4) alkyl, C3_, cycloalkyl, cyano, hydroxy group, etc.), etc., and the number of the substituents are preferably 1 to 3.
Among others, as Rz, an optionally substituted acyclic hydrocarbon group (e. g., alkyl, alkenyl, etc., each of which may be substituted) is preferable, an optionally substituted lower C1_6 alkyl group is more preferable, and in particular, an optionally substituted methyl group is preferable.
As R3, an optionally substituted alicyclic hydrocarbon group (e. g., cycloalkyl, cycloalkenyl, etc., each of which may be substituted; preferably, an optionally substituted lower C3_8 cycloalkyl group; and more preferably, an optionally substituted cyclohexyl) or an optionally substituted alicyclic heterocyclic group (preferably, an optionally substituted saturated alicyclic heterocyclic group (preferably, 6-membered ring group); more preferably, an optionally substituted tetrahydropyranyl, an optionally substituted tetrahydrothiopyranyl or an optionally substituted piperidyl; an in particular, an optionally substituted tetrahydropyranyl) is preferable.
As the compound represented by the above formula (I), 7-(4-ethoxyethoxyphenyl)-1-ethyl-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide, 1-ethyl-7-(4-propoxyethoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide, 7-(4-butoxyethoxyphenyl)-1-ethyl-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]'2,3-dihydro-1-benzazepine-4-carboxamide, 7-(4-ethoxythoxyphenyl)-1-formyl-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide, 1-formyl-7-(4-propoxyethoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-rl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide, 7-(4-butoxyethoxyphenyl)-1-formyl-N-[4-[[N-methyl-N
(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1 benzazepine-4-carboxamide, 7-(4-butoxyethoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-5-yl)amino]methyl]phenyl]-1-propyl-2,3-dihydro-1-benzazepine-4-carboxamide, N-[4-[[N-methyl-N-(tetrahydropyran-5-yl)amino]methyl]phenyl]-7-(4-propoxyethoxyphenyl)-1-propyl-2,3-dihydro-1-benzazepine-4-carboxamide, 1-benzyl-7-(4-butoxyethoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide, 7-(4-butoxyethoxyphenyl)-1-cyclopropylmethyl-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide, 7-(4-butoxyethoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1-phenyl-2,3-dihydro-1-benzazepine-4-carboxamide, 7-(4-butoxyethoxyphenyl)-1-(3,4-methylenedioxy)phenyl-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide, 7-(4-butoxyethoxyphenyl)-1-(2-methyloxazol-5-yl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide, 1-allyl-7-(4-butoxyethoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide, 7-(4-butoxyethoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1-(3-thienyl)methyl-2,3-dihydro-1-benzazepine-4-carboxamide, 7-(4-butoxyethoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1-(thiazol-2-yl)methyl-2,3-dihydro-1-benzazepine-4-carboxamide, 7-(4-butoxyethoxyphenyl)-1-(1-methylpyrazol-4-yl)methyl-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide, 7-(4-butoxyethoxyphenyl)-1-(3-methylisothiazol-4-yl)methyl-N-[4-[[N-methyl-N-(tetrahydropyran-5-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide, 7-(4-butoxyethoxyphenyl)-1-(1-ethylpyrazol-4-yl)methyl-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide, 7-(4-butoxyethoxyphenyl)-1-isobutyl-N-[4-[[N-methyl-N-(tetrahydropyran-5-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide, 1-isobutyl-N-[4-[[N-methyl-N-(tetrahydropyran-5-yl)amino]methyl]phenyl]-7-(4-propoxyethoxyphenyl)-2,3-dihydro-1-benzazepine-4-carboxamide, 7-(4-butoxyethoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1-(thiazol-5-yl)methyl-2,3-dihydro-1-benzazepine-4-carboxamide, 7-(4-butoxyethoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1-(1-5~
methyltetrazol-5-yl)methyl-2,3-dihydro-1-benzazepine-4-carboxamide, 7-(4-butoxyethoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1-(2-methyltetrazol-5-yl)methyl-2,3-dihydro-1-benzazepine-4-carboxamide etc. are preferable.
Examples of the salts of the compound represented by the formula (I) include a pharmaceutically acceptable salt such as a salt with inorganic base, a salt with organic base, a salt with inorganic acid, a salt with organic acid, a salt with basic or acidic amino acid, etc.
Suitable examples of the salt with the inorganic base include a salt with alkali metal (e. g. sodium, potassium, etc.), alkaline earth metal (e. g. calcium, magnesium, etc.), aluminum, ammonium, etc. Suitable examples of the salt with the organic base include a salt with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N,N' -dibenzylethylenediamine, etc.
Suitable examples of the salt with the inorganic acid include a salt with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc.
Suitable examples of the salt with the organic acid include a salt with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, malefic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. Suitable examples of the salt with the basic amino acid include a salt with arginine, lysine, ornithine, etc. Suitable examples of the salt with the acidic amino acid include a salt with aspartic acid, glutamic acid, etc. The compound of the formula (I) of the present invention may be hydrated or non-hydrated. When the compound of the formula (I) of the present invention exists as configuration isomer, diastereomer, conformer, etc., it is possible to isolate individual isomers with a per se known separation and purification method, if desired. When the compound of the formula (I) of the present invention is racemate, it can be separated into (S)-isomer and (R)-isomer with usual optical resolution and individual optical isomers and a mixture thereof are included in the scope of the present invention.
The pro-drug of the compound of the formula (I) or a salt thereof of the present invention [hereinafter, referred to as Compound (I) in some cases] means a compound which is converted to Compound (I) under the physiological condition or with a reaction due to an enzyme, an gastric acid, etc. in the living body, that is, a compound which is converted to Compound (I) with oxidation, reduction, hydrolysis, etc. according to an enzyme: a compound which is converted to Compound (I) with hydrolysis by gastric acid, etc.; etc. Examples of the pro-drug of Compound (I)include a compound wherein an amino group of Compound (I) is substituted with acyl, alkyl, phosphoric acid, etc. (e.g. a compound wherein an amino group of Compound (I) is substituted with eicosanyl, alanyl, pentylaminocarbonyl, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonyl, tetrahydrofuranyl, pyrrolidylmethyl, pivaloyloxymethyl, tert-butyl, etc,): a compound wherein an hydroxy group of Compound (I) is substituted with acyl, alkyl, phosphoric acid, boric acid, etc. (e.g. a compound wherein an hydroxy group of Compound (I) is modified with acetyl, palmitoyl, propanoyl, pivaloyl, succinyl, fumaryl, alanyl, dimethylaminomethylcarbonyl, etc.): a compound wherein a carboxyl group of Compound (I) is modified with ester, amide, etc. (e.g. a compound wherein a carboxyl group of Compound (I) is modified with ethyl ester, phenyl ester, carboxymethyl ester, dimethylaminomethyl ester, pivaloyloxymethyl ester, ethoxycarbonyloxyethyl ester, phthalidyl ester, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl ester, cyclohexyloxycarbonylethyl ester, methyl amide, etc.): etc. These pro-drugs can be produced by per se known method from Compound (I).

The pro-drug of Compound (I) may be a compound which is converted into Compound (I) under the physiological conditions as described in "Pharmaceutical Research and Development" , Vol.7 (Drug Design), pages 163-198 published in 1990 by Hirokawa Publishing Co.
Compound (I) may be labeled with isotope (e.g. 3H, i9C, 355, ~zsl~ etc) , etc.
The present compound of the formula (I) or a salt thereof alone or as an admixture with a pharmaceutically acceptable carrier (e.g. solid formulations such as tablets, capsules, granules, powders, etc.; liquid formulations such as syrups, injections, etc.) may be orally or non-orally (preferably orally) administered.
Examples of non-oral formulations include injections, drops, suppositories, pessaries, etc. In particular, pessary is useful for the prevention of infectious diseases of HIV.
Examples of the carriers include various organic or inorganic carriers which are generally used in this field.
For example, an excipient, a lubricant, a binder, a disintegrating agent, etc. are used in solid formulations, and a solvent, a solubilizer, a suspending agent, an isotonizing agent, a buffer, a soothing agent, etc. are used in liquid formulations. In addition, if desired, an appropriate additive such as a preservative, an antioxidant, a colorant, a sweetener, etc. may be used.
Suitable examples of the excipient include lactose, sucrose, D-mannitol, starch, crystalline cellulose, light silicic acid anhydride, etc. Suitable examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica, etc. Suitable examples of the binder include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinyl-pyrrolidone, etc. Suitable examples of the disintegrating agent include starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, sodium carboxymethyl starch, etc.
Suitable examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, etc. Suitable examples of the solubilizer include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, etc.
Suitable examples of the suspending agent include surfactants such as stearyl triethanolamine, sodium laurylsulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzetonium chloride, glycerin monostearate, etc.~ hydrophilic polymers such as polyvinylalcohol, polyvinylpyrrolidone, sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose hydroxyethyl cellulose, hydroxypropyl cellulose, etc. Suitable examples of the isotonizing agent include sodium chloride, glycerin, D-mannitol, etc. Suitable examples of the buffer include a buffer solution of 5 phosphate, acetate, carbonate, citrate, etc. Suitable examples of the soothing agent include benzylacohol, etc.
Suitable examples of the preservative include paraoxybenzoic acid esters, chlorobutanol, benzylalcohol phenethylalcohol, dehydroacetic acid, sorbic acid, etc.
10 Suitable examples of the antioxidant include sulfites, ascorbic acid, etc.
The present invention further provides production methods of the compound of the formula (I) or a salt thereof.
15 The compound of the formula (I) or a salt thereof can be produced in accordance with per se known methods, for example, the methods described in JP-A-73476/1996, or analogous methods thereto, etc.
A salt of the compound of the formulas (II), (III), 20 (IV), (V), (I-1) and (I-2)(hereinafter, abbreviated as Compound(II), Compound(III), Compound(IV), Compound(V), Compound(I-1) and Compound(I-2), respectively, in some cases) may be similar to that of Compound (I).
In the following reactions, when the starting 25 compounds have, as substituents, amino group, carboxyl group and/or hydroxy group, these groups may be protected by conventional protective groups such as those generally employed in peptide chemistry, etc. After the reaction, if necessary, the protective groups may be removed to obtain the desired compound.
Examples of an amino-protective group include an optionally substituted Cl_6 alkylcarbonyl (e. g., acetyl, propionyl, etc.), formyl, phenylcarbonyl, C1_6 alkyloxycarbonyl (e. g., methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, etc.), phenyloxycarbonyl (e. g., benzoxycarbonyl, etc.), C~_lo aralkyloxycarbonyl (e. g., benzyloxycarbonyl, etc.), trityl, phthaloyl, etc. These protective groups may be substituted by 1 to 3 substituents such as halogen atom (e. g., fluorine, chlorine, bromine, iodine, etc.), C1_6 alkylcarbonyl (e. g., acetyl, propionyl, butyryl, etc.), nitro group, etc.
Examples of a carboxyl-protective group include an optionally substituted C1_6 alkyl (e. g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.), phenyl, trityl, silyl, etc. These protective groups may be substituted by 1 to 3 substituents such as halogen atom (e. g., fluorine, chlorine, bromine, iodine, etc.), C1_6 alkylcarbonyl (e. g., acetyl, propionyl, butyryl, etc.), formyl, nitro group, etc.
Examples of a hydroxy-protective group include an optionally substituted C1_6 alkyl (e. g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.), phenyl, C,_lo aralkyl (e. g., benzyl, etc.), C1_6 alkylcarbonyl (e. g., acetyl, propionyl, etc.), formyl, phenyloxycarbonyl, C,_lo aralkyloxycarbonyl (e. g., benzyloxycarbonyl, etc.), pyranyl, furanyl, silyl, etc. These protective groups may be substituted by 1 to 4 substituents such as halogen atom (e. g., fluorine, chlorine, bromine, iodine, etc.), C1_6 alkyl, phenyl, C7_lo aralkyl, nitro group, etc.
These protective group may be introduced or removed by per se known methods (e.g. a method described in Protective Groups in Organic Chemistry (J.F.W. McOmie et al.; Plenum Press Inc.). For example, employable method for removing the protective groups is a method using an acid, a base, reduction, ultraviolet ray, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, etc.
[Method A]

Y
C~~H + I i Nw 3 R
UO ~ UiO
Condensation .
I H
R ~ i' .- iN R2 C
fl ~~) 0 ~ N\ 3 R
wherein each symbol is as defined above.
This production method is carried out by reacting Compound (II) with Compound (III) to obtain the anilide Compound (I).
The condensation reaction of Compounds (II) and (III) is carried out by usual methods for peptide synthesis. Said methods for peptide synthesis are employed according to optional known methods, for example, methods described in " Peptide Synthesis" written by M.
Bodansky and M. A. Ondetti, Interscience, New York, 1966; " The Proteins" , volume 2, written by F. M. Finn and K. Hofmann, H. Nenrath and R. L. Hill edition, Academic Press Inc., New York,1976; "peputido-gosei no kiso to jikken (Basis and Experiment of Peptide Synthesis)" written by Nobuo lzumiya et al., Maruzen K.K., 1985;etc., as well as azide method, chloride method, acid anhydride method, mixed acid anhydride method, DCC
method, active ester method, method using Woodward reagent K, carbonyldiimidazole method, oxidation-reduction method, DCC/HONB method, etc. and in addition WSC method, method using diethyl cyanophosphate (DEPC), etc. The condensation reaction can be carried out in a solvent.
Examples of the solvents to be employed in the reaction include anhydrous or hydrous N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), pyridine, chloroform, dichloromethane, tetrahydrofuran (THF), dioxane, acetonitrile, or a suitable mixture of these solvents.
Usually, about 1-2 moles of the Compound (III) are used per 1 mole of the Compound (II). The reaction temperature is generally about -20°C to about 50°C, preferably about -10°C to about 30°C and the reaction time is generally about 1 to about 100 hours, preferably about 2 to about 40 hours. The thus obtained anilide derivative (I) can be isolated and purified by known separation and purification methods such as concentration, concentration under reduced pressure, extraction, crystallization, recrystallization, solvent convert, chromatography, etc.
In addition, the compound of the formula (II) or a 5 salt thereof is a novel compound and useful as an intermediate for producing the compound of the formula (I) or a salt thereof.
[Method B]
V
i _ ~N Rz C
U-O 0 I i N~
H
or Y
H
R ~ ~ ''- iN H
C
n 0 ,~ N ~ 3 R
(1) tertiary amination, or (2) reductive animation v H
R iN w Rz 0 I ~ N
O) wRs (1) Compound (I) can be produced by reacting Compound (I-1) or (I-2) with halogenated alkyl or halogenated aralkyl.
Examples of a halogen atom include chlorine, bromine, iodine, etc. and usually about 1 to 2 moles of the halogenated alkyl or halogenated aralkyl is used per mole of Compound (I-1) or (I-2). If necessary, the reaction smoothly proceeds by addition of about once to thrice moles of a base such as triethylamine, diisopropylethylamine, pyridine, lithium hydride, sodium . CA 02380860 2001-12-03 hydride, sodium methoxide, sodium ethoxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate and further sodium iodide, potassium iodide, etc.
This tertiary amination reaction is carried out in an inert solvent such as methanol, ethanol, propanol, isopropanol, n-butanol, tetrahydrofuran, diethyl ether, dimethoxyethane, 1,4-dioxane, toluene, benzene, xylene, dichloromethane, chloroform, 1,2-dichloroethane, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), pyridine, etc., or a mixture of these solvents. The reaction temperature is generally about 0°C to 180°C, and the reaction time is generally about 1 hour to about 40 hours. This reaction is preferably carried out under inert gas (e. g. nitrogen. argon, etc.) atmosphere.
(2) Compound (I) having a tertiary amino can be produced by reacting Compound (I-1) or (I-2) with an aldehyde compound in the presence of a reductive animation reagent such as triacetoxysodium borohydride, sodium cyanoborohydride, sodium borohydride, etc. The conditions of this reductive amination reaction vary depending on the reagent to be used. For example, when sodium triacetoxyborohydride is used, reaction is carried out in an inert solvent such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, diethyl ether, dioxane, acetonitrile, dimethylformamide (DMF), etc., or a mixture of these solvents. In this case, about 1 to 2 moles of the reagent is used per mole of Compound (I-1) or (I-2). The reaction temperature is generally about 0°C to about 80°C, and the reaction time is generally about 1 hour to about 40 hours. This reaction is preferably carried out under inert gas (e. g. nitrogen, argon, etc.) atmosphere.
[Method C]
V
H
R. CiN w U v> 0 I i V
Substitution Y
w I H
R ~ ~ ._...- ~N R 2 C
I~
0 ,,~ N~ 3 R
wherein V in the Compound (IV) is a halogen atom (chlorine, bromine, iodine, etc.), or a sulfonyloxy group (methanesulfonyloxy group, trifluoromethanesulfonyloxy group, benzenesulfonyloxy group, toluenesulfonyloxy group, etc.), and the other symbols are as defined above.
Compound (I) having a tertiary amino group can be produced by reacting Compound (IV) and a secondary amine compound. Usually, about 1 to 3 moles of the secondary amine compound is used per mole of Compound (IV). If necessary, the reaction smoothly proceeds by addition of about once to thrice moles of a base such as triethylamine, diisopropylethylamine, pyridine, lithium hydride, sodium hydride, sodium methoxide, sodium ethoxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate and further sodium iodide, potassium iodide, etc. This substitution reaction is carried out in an inert solvent such as methanol, ethanol, propanol, isopropanol, n-butanol, tetrahydrofuran, diethyl ether, dimethoxyethane, 1,4-dioxane, toluene, benzene, xylene, dichloromethane. chloroform, 1,2-dichloroethane, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), pyridine, etc., or a mixture of these solvents. The reaction temperature is generally about -10°C to about 180°C, and the reaction time is generally about 1 hour to about 40 hours. The reaction is carried out preferably under inert gas (e. g. nitrogen, argon, etc.) atmosphere.
[Method D]

Y
w I H
V ~ .~ _- iN R 2 C
Cv) ~ ~ I
0 --' R
Suzuki reaction Y
I H
R ~ .i ~,- ,~N R 2 C ~ I
it o .~ ~u~ 3 R
wherein V' in Compound (V) is a halogen atom (bromine, iodine, etc.) or a sulfonyloxy group (trifluoromethanesulfonyloxy group, etc.), and the other 5 symbols are as defined above.
Compound (I) wherein the group R1 is a 5- to 6-membered aromatic ring group can be produced by subjecting Compound (V) to, for example, Suzuki reaction [cross condensation reaction of aryl borate with e.g.
10 aryl halide or aryloxytrifluoromethane-sulfonate in the presence of a palladium catalyst; A. Suzuki et al., Synth.
Commun. 1981, 111, 513J. Usually, about 1-1.5 times moles of aryl borate is used per mole of Compound (V) to obtain Compound (I).
The thus obtained Compound (I) can be isolated and purified by known separation and purification methods such as concentration, concentration under reduced pressure, extraction, crystallization, recrystallization, solvent convert, chromatography, etc.
Compound (II) used as a starting material can be produced by a known method (e.g. method described in JP-A-73476/1996, etc.) or the methods analogous thereto.
For example, Compound (II) can be produced by a method described in the following Reaction Scheme I or II, a method described in the following Reference Examples or the methods analogous thereto.
Reaction Scheme I

5' R 5, I~ (CH ) COOH R

_ i \
R ~ \ I CCH~) 3 (vi) R~ \
(VII) R5, R5, N
/ ~ CCH2) z ,..,~ ~' I ~ CCH2) 2 1 \ ~ 9 1 \ 9 R ~~ COOR R ''~ ~' 'COOK
(vi I I) OH (Ix) R~~ 5, R
.I
.. / CCH~) 2 .---,.,~ ~ N' CCH ) 1 \ ~ / g ~ 2 2 R coon R' '~ ' cooH
(x> (II) wherein R9 is a C1_4 alkyl group, R5 has the same meaning as the substituent represented by R5, and the other symbols are as defined above.
In this reaction, the Compound (VI) is heated with polyphosphoric acid, or Compound (VI ) is converted to acid chloride with thionyl chloride, oxalyl chloride, phosphorus oxychloride, phosphorus pentachloride, etc., followed by subjecting the resulting acid chloride to usual Friedel-Crafts reaction and cyclizing the same to produce Compound (VII). Compound (VII) is then reacted with carbonate ester in the presence of a base to produce ketoester (VIII). Compound (VIII) is subjected to reduction with catalytic hydrogenation or sodium borohydride, etc. to produce Compound (IX). Compound (IX) is subjected to dehydration by the conventional method to produce Compound (X). Compound (X) is subjected to ester hydrolysis to produce unsaturated carboxylic acid (II).
Reaction Scheme II
5' R
(CH ) COORg 5' \ ~ Dieckmann condensation R W ~a CW - COOK ) ~ \ , s R '~' '~ ''COOK
~W ' CH0 ~ ~~ O Cv i i ~ ) R
(CH2) Z
1 \ ( ~9 R ~ ~ ~COOR
OH {x~

(X) Rs, R5, N, ~CH2) z ---. i I N~ (CH?) 2 C R9 R~ \ ~ COOH

SIX) III) wherein R1° is C1_4 alkyl group and the other symbols are as defined above.
The Compound (VIII) or (IX) can be produced by subjecting the Compound (XII) to Dieckmann condensation (J. P. Schaefer and J. J. Bloomfield, Org. Reactions, 1967, 15, 1). Compound (VIII) or (IX) is subjected to the reactions as described in Reaction Scheme I to produce unsaturated carboxylic acid (II).
Compound (III) can be produced by a known method (e.g. method described in JP-A-73476/1996, etc.) or the methods analogous thereto. For example, Compound (III) can be produced by a method described in the following Reaction Scheme III, a method described in the following Reference Examples or the methods analogous thereto.
Reaction Scheme 111 ~N
CXIII) R
Reduction H N RZ
(I I !) R
The reduction of Compound (XIII) can be carried out by per se known methods, for example, reduction with metal, reduction with metal hydride, reduction with metal hydride complex compound, reduction with metal hydride complex compound, reduction with diborane or substituted borane, catalytic hydrogenation, etc. That is, this reaction is carried out by treating Compound (XIII) with a reducing agent. Examples of the reducing agent include metal such as reduced iron, zinc powder, etc.; alkali metal borohydride (e. g., sodium borohydride, lithium borohydride, etc.): metal hydride complex compound such as aluminum lithium hydride, etc.; metal hydride such as sodium hydride etc.; organic tin compound (triphenyltin hydride, etc.), metal complex compound and metal salt such as nickel compound, zinc compound etc.: catalytic ~

reducing agent using hydrogen and transition metal catalyst such as palladium, platinum, rhodium, etc.:
diborane; etc. Among others, as the reducing agent, catalytic reducing agent using hydrogen and transition metal catalyst such as palladium, platinum, rhodium, etc.; metal such as reduced iron, etc. are preferable.
The reaction is carried out in a solvent which does not affect the reaction. Examples of the solvent include benzene, toluene, xylene, chloroform, carbon tetrachloride, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, diethyl ether, tetrahydrofuran, dioxane, methanol, ethanol, propanol, isopropanol, 2-methoxyethanol, N,N-dimethylformamide, acetic acid, or a mixture of these solvents, etc. The solvent is appropriately selected depending on kind of the reducing agent. The reaction temperature is generally about -20°C
to about 150°C, preferably about 0°C to about 100°C, and the reaction time is generally about 1 to about 24 hours.
The thus resulted Compound (II) or (III) can be separated and purified with know separation and purification methods such as concentration, concentration under reduced pressure, extraction, crystallization, solvent conversion, chromatography, etc.
The compound of the formula (I) or a salt thereof of the present invention may be used in combination with other drug for the treatment or prevention of infectious diseases of HIV (in particular, a pharmaceutical composition for the treatment or prevention of AIDS). In this case, these drugs can be formulated by mixing individually or simultaneously with pharmaceutically acceptable carriers, excipients, binders, diluents or the like, which can be administered orally or non-orally as a pharmaceutical composition for the treatment or prevention of infectious diseases of HIV. In the case of formulating these effective components individually, while the individually formulated agents can be administered in the form of their mixture prepared by using e.g. a diluent when administered, the individually formulated agents can also be administered separately or simultaneously or with time intervals to the one and same subject. A kit for administering the individually formulated effective components in the form of their mixture prepared by using e.g., a diluent when administered (e. g., a kit for injection which comprises two or more ampoules each comprising a powdery component and a diluent for mixing and dissolving two or more components when administered, etc.), a kit for administering the individually formulated agents simultaneously or with time intervals to the one and the same subject (e. g., a kit for tablets to be administered simultaneously or with time intervals, characterized by having two or more tablets each comprising an agent and said tablets being put in one or separate bags and, if necessary, a column to describe time to be administered each agent, etc.), etc. are also included by the pharmaceutical composition of the present invention.
Example of the other pharmaceutical agent for the treatment or prevention of infectious disease of HIV to be used in combination with the compound of the formula (I) or a salt thereof of the present invention include nucleotide reverse transcriptase inhibitors such as zidovudine, didanosine, zalcitabine, lamivudine, stavudine, abacavir, adefovir, adefovir dipivoxil, fozivudine tidoxil, etc.; non-nucleotide reverse transcriptase inhibitors (including an agent having anti-oxidation activity such as immunocal, oltipraz, etc.) such as nevirapine, delavirdine, efavirenz, loviride, immunocal, oltipraz, etc.: protease inhibitors such as saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, palinavir, lasinavir, etc.; etc.
As the nucleotide reverse transcriptase inhibitor, zidovudine, didanosine, zalcitabine, lamivudine, stavudine, etc. are preferable; as the non-nucleotide reverse transcriptase inhibitor, nevirapine, delavirdine etc. are preferable; and as the protease inhibitor, saquinavir, ritonavir, indinavir, nelfinavir etc. are preferable.
The compound of the formula (I) or a salt thereof of the present invention may be used in combination with, for example, CXCR4 antagonist (CXCR4 being a second receptor of T cell-tropic HIV-1) such as AMD-3100, etc., antibody against HIV-1 surface antigen. HIV-1 vaccine, etc., in addition to the above-mentioned protease inhibitor, nucleotide reverse transcriptase inhibitor, etc.
The compound of the formula (I) or a salt thereof of the present invention has CC chemokine receptor (CCR) antagonistic activity, in particular, potent CCR5 antagonistic activity and, therefore, can be used for the treatment or prevention of various infectious diseases of HIV, for example, AIDS in human. The compound of the formula (I) or a salt thereof of the present invention is low toxic and safely used.
The compound of the formula (I) or a salt thereof of the present invention can be used as CCR5 antagonist for the treatment or prevention of AIDS and also for the prevention of the progression of the AIDS.
The dose per day of the compound of the formula (I) or a salt thereof varies depending on the condition and body weight of a patient, administration route, etc.

Typical daily dose per adult patient (body weight: 50Kg) for oral administration is about 5-1000mg, preferably about 10-600mg, more preferably about 10-300mg, and in particular about 15-150mg, as active ingredient [the 5 compound of the formula (I) or a salt thereof] and the compound of the formula (I) or a salt thereof is administered once or 2-3 times per day.
When the compound of the formula (I) or a salt thereof is used in combination with a reverse 10 transcriptase inhibitor and/or a protease inhibitor. The dose of the reverse transcriptase inhibitor or the protease inhibitor ranges, for example, from about 1/200-1/2 or more of usual dose to about 2-3 times or less of usual dose. In case that two or more drugs are used in 15 combination, each dose of the drugs is appropriately adjusted if one drug affects metabolism of the other drug, while each dose of the drugs when they are used in combination is generally the same as the dose when they are used alone.
20 Usual doses of the typical reverse transcriptase inhibitors and the protease inhibitors are as follows:
zidovudine . 100mg didanosine . 125-200mg zalcitabine . 0.75mg 25 lamivudine . 150mg stavudine . 30-40mg saquinavir . 600mg ritonavir . 600mg indinavir . 800mg nelfinavir . 750mg In case of combination use of the compound of the formula (I) or a salt thereof with a reverse transcriptase inhibitor and/or a protease inhibitor;
preferred embodiments are shown below.
(1) A drug containing about 10-300mg of the compound of the formula (I) or a salt thereof and a drug containing about 50-200mg of zidovudine to one adult patient (body weight: 50Kg) are administered. Each of the drugs may be administered to the one and the same subject simultaneously or with time intervals of 12 hours or less.
(2) A drug containing about 10-300mg of the compound of the formula (I) or a salt thereof and a drug containing about 300-1200mg of saquinavir to one adult patient (body weight: 50Kg) are administered. Each of the drugs may be administered to the one and the same subject simultaneously or with time intervals of 12 hours or less.
Best Mode for Carrying out the Invention The present invention is hereinafter described in more detail by means of the following Test Example.

~

Formulation Example, Reference Examples and Working Examples, which are mere examples of the present invention and are not construed as limitative to the present invention.
The following gene manipulation is carried out in accordance with methods described in textbook (Maniatis et al., Molecular Cloning, Cold Spring Harbor Laboratory, 1989) or protocol attached to reagents.
Examples Test Example (1) Cloning of human CCRS chemokine receptor Cloning of CCR5 gene was carried out by a PCR method from human spleen cDNA. With using 0.5ng of spleen cDNA
(Toyobo, QUICK-Clone cDNA) as template, PCR was performed in DNA Thermal Cycler 480 (Perkin-Elmer) (reaction conditions: 30 cycles of 95°C for 1 minute, 60°C for 1 minute, and 75°C for 5 minutes) by adding each 25 pmol of primers of a primer set, SEQ ID NO.: 1 described in Test Example (1) of WO
99/32100 [length of sequence: 34; type of sequence:
nucleic acid; strandedness: single; topology: straight;
kind of sequence: other nucleic acid synthetic DNA, and SEQ ID NO.: 2 described in Test Example (1) of WO
99/32100 [length of sequence: 34; type of sequence:

nucleic acid; strandedness: single; topology: straight;
kind of sequence: other nucleic acid synthetic DNA
which were designed referring to nucleotide sequence of CCR5 gene reported by Samson et. al. (Biochemistry, 35(11), 3362-3367 (1996)) and by using TaKaRa EX Taq (Takara Shuzo). The resultant PCR product was subjected to agarose gel electrophoresis to collect about l.Okb DNA
fragment, which was subjected to Original TA Cloning Kit (Funakoshi) to carry out cloning of CCR5 gene.
(2) Preparation of plasmid for expression of human CCR5 The plasmid obtained in the above (1) was digested with restriction enzymes Xbal (Takara Shuzo) and BamHI
(Takara Shuzo) and subjected to agarose gel electrophoresis to collect about l.Okb DNA fragment.
The DNA fragment was mixed with plasmid pcDNA3.1 (Funakoshi) for expression in animal cells, said plasmid being digested with Xbal and BarnHI, and they were ligated with DNA Ligation Kit Ver.2 (Takara Shuzo). The resulting plasmid was subjected to transformation of competent cell of E. coli JM109 (Takara Shuzo) to obtain plasmid pCKR5.
(3) Introduction of plasmid for expression of human CCR5 into CHO-K1 cell and Expression of said plasmid in CHO-K1 cell CHO-Kl cells were grown in 750m1 of tissue culture flask (Becton Dickinson) using Ham' s F12 medium (Nikon Pharmaceutical) containing 10o fetal calf serum (Life Tech Oriental) and took off with 0.5g/L trypsin-0.2g/L
EDTA (Life Tech Oriental). The cells were washed with PBS (Life Tech Oriental), centrifuged (1000rpm, 5 minutes), and suspended in PBS. With using Gene Pulser (Bio-Rad Laboratories), DNA was introduced into the cells under the conditions shown below. That is, to the cuvette of 0.4cm gap were added 8 x 106 cells and 10~g of plasmid pCKR5 for expression of human CCR5, and electroporation was carried out under 0.25kV of voltage and 960~F of capacitance. The cells were transferred into Ham' s F12 medium containing 10o fetal calf serum, and cultivated for 24 hours. The cells were again took off and centrifuged, and suspended in Ham' s F12 medium containing 10~ fetal calf serum and 500~g/ml of geneticin (Life Tech Oriental). The suspension was diluted to give 104 cells/ml of the suspension, which was inoculated on 96 well plate (Becton Dickinson) to give geneticin resistant cells.
The resulting geneticin resistant cells were cultivated in 96 well plate (Becton Dickinson), and cells expressing CCR5 were selected from the geneticin resistant cells. That is, in assay buffer (Ham' s F12 medium containing 0.5~ BSA and 20mM HEPES (Wako Pure Chemical, pH7.2)) to which was added 200pM of [lzsl]-RANTES (Amersham) as a ligand, a binding reaction was carried out at room temperature for 40 minutes, and the buffer was washed with cooled PBS. To the buffer was 5 added 50~1/well of IM NaOH, and the mixture was stirred.
Radioactivity was determined with a y-counter to select CCRS/CHO cells which specifically bind to the ligand.
(4) Evaluation of Test Compounds based on CCR5 antagonistic activity 10 The CCRS/CHO cells were inoculated on 96 well microplate (5 x 104 cells/well) and cultivated for 24 hours. The medium was removed by means of suction, and to each well was added an assay buffer containing Test Compound (1~M) and then 100pM of [lzsl]_RANTES (Amersham) 15 as a ligand. A binding assay was carried out at room temperature for 40 minutes, and an assay buffer was removed by means of suction. Each well was washed twice with cooled PBS, and 2001 of Microscint-20 (Packard Instrument, Inc.) was added to each well. Radio-activity 20 was determined with Top-Count Micro Scintillation Counter (Packard Instrument, Inc.).
According to the method described above, inhibitory rate of Test Compound to CCR5 binding was measured. The results are shown in Table 1.

Table 1 Compound Number Inhibitory Rate (5) Inhibitory effect on HIV-1 infection to MAGI-CCR5 cell The plasmid where ~-galactosidase gene was ligated downstream of HIV-1 LTR was introduced into CD4 positive HeLa cell, to which human CCR5 was further introduced to obtain transformant MAGI-CCR5.
By using said transformant MAGI-CCR5, a degree of HIV-1 infection was calculated using ~-galactosidase activity (blue color due to decomposition of 5-bromo-4-chloro-3-indolyl-~-D-galactopyranoside) as an index.
Specifically, MAGI-CCR5 cells were suspended in DMEM
medium containing l0% serum to prepare 5 x 104 cells/ml suspension. To each well of 96 well plate was inoculated 2001 of the suspension, and the cells were cultivated at 37°C overnight. The medium was removed by means of suction, and to the residue was added 1001 of the above medium containing 1.6~M of Test Compound and 1001 of the above medium containing 300PFU of HIV-1 BA-L cells. The cells were cultivated at 37°C for 2 days. The medium was removed by means of suction. To the residue was added 2001 of a cell fixative (PBS containing 1% formaldehyde and 0.2% glutaraldehyde), and the mixture was allowed to stand at room temperature for 5 minutes and washed twice with PBS. To the mixture was added 1001 of staining solution (PBS containing 4~M potassium ferrocyanide, 4~M

potassium ferricyanade, 2~M MgCl2 and 0.4mg/ml X-gal), and the mixture was allowed to stand at 37°C for 50 minutes and washed twice with PBS. The number of blue cells was counted by a microscope and defined as the number of cells infected with HIV-1. According to this method, inhibition rate on HIV-1 infection was determined.
The results are shown in Table 2.
Table 2 Compound Number Inhibitation Rate The pharmaceutical composition for antagonizing CCR5 (e.g., a medicament for the treatment or prevention of infectious disease of HIV, a medicament for the treatment or prevention of AIDS, etc.) comprising the compound of the formula (I) or a salt thereof of the present invention, as an active ingredient, can be prepared, for example, by the following prescriptions:
Formulation Example 1. Capsule (1) Compound obtained in Working Example 1 40mg (2) lactose 70mg (3) fine crystalline cellulose 9mg (4) magnesium stearate 1mg 1 capsule 120mg (1), (2), (3) and 1/2 of (4) are mixed and then granulated. To the granules is added the remainder of (4), and the whole is filled into a gelatin capsule.
2. Tablet (1) Compound obtained in Working Example 1 40mg (2) lactose 58mg (3) corn starch l8mg (4) fine crystalline cellulose 3.5mg (5) magnesium stearate 0.5mg 1 capsule 120mg (1), (2), (3), 2/3 of (4) and 1/2 of (5) are mixed and then granulated. To the granules are added the remainders of (4) and (5), followed by subjecting the mixture to compression molding.
Reference Example 1 In DMF (14m1) was dissolved 1- formyl-7-(4-morpholinophenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.18g). To the solution was added, under ice-cooling, thionyl chloride (0.1m1), and the mixture was stirred at room temperature for 30 minutes.
Under reduced pressure, the solvent was evaporated, and the residue was suspended in THF (50m1). The suspension was added dropwise to a solution of 4-[N-methyl-N-(tetrahydro-2H-pyran-4-yl)aminomethyl]aniline (0.13g) and triethylamine (0.33m1) in THF (5m1), under ice-cooling, and the mixture was stirred under nitrogen atmosphere at 5 room temperature for 2 hours. Under reduced pressure, the solvent was evaporated. To the residue was added water, and the mixture was extracted with ethyl acetate.
The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the 10 solvent was evaporated to give crude crystals, which were recrystallized from ethanol/hexane to give 1-formyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-7-(4-morpholinophenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.16g) as 15 colorless crystals.
mp 234 - 243°C.
1H-NMR (8 ppm, CDC13) 1.70 - 1.75 (4H, m), 2.21 (3H, s), 2.60 - 2.67 (1H, m), 3.03 (2H, t, J = 5.4 Hz), 3.21 - 3.26 (4H, m) , 3. 37 (2H, dt, J = 2.8, 11.2 Hz) , 3.58 (2H, s) , 20 3.87 - 3.95 (6H, m), 4.02 - 4.07 (2H, m), 7.00 (2H, d, J =
8.8 Hz), 7.19 (1H, d, J = 8.6 Hz), 7.32 (2H, d, J = 8.4 Hz), 7.47 - 7.59 (7H, m), 7.69 (1H, d, J = 2.2 Hz), 8.55 (1H, s).
IR (KBr) v: 2953, 2845, 1667 cml.
Anal. Calcd. for C35HaoNa09: C, 72.39: H, 6.94 N, 9.65.
25 Found C, 72.03 H, 6.65 N, 9.49.

Reference Example 2 In DMF (5m1) was dissolved 7-(4-ethoxyphenyl)-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.2g). To the solution was added, under ice-cooling, thionyl chloride (O.llml), and the mixture was stirred at room temperature for 30 minutes. Under reduced pressure, the solvent was evaporated, and the residue was suspended in THF (15m1). The suspension was added dropwise to a solution of 4-[N-methyl-N-(tetrahydro-2H-pyran-4-yl)aminomethyl]aniline (0.15g) and triethylamine (0.41m1) in THF (5m1), under ice-cooling, and the mixture was stirred under nitrogen atmosphere at room temperature overnight. Under reduced pressure, the solvent was evaporated. To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated to give crude crystals, which were recrystallized from ethyl acetate/hexane to give 7-(4-ethoxyphenyl)-1-formyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.25g) as colorless crystals.
mp 211 - 215°C.
1H-NMR (b ppm, CDC13) 1. 45 (3H, t, J = 6. 9 Hz) , 1. 59 - 1.75 (4H, m), 2.21 (3H, s), 2.60 - 2.68 (1H, m), 3.04 (2H, t, J

- 5.5 Hz), 3.37 (2H, dt, J = 2.8, 11.3Hz),3.58 (2H, s), 3.93 (2H, t, J = 5.5 Hz),4.01 - 4.18 (4H,m), 6.99 (2H, d, J = 8.8 Hz), 7.19 (1H, J = 8.6 Hz), 7.32(2H, d, J = 8.4 d, Hz), 7.46 - 7.58 (6H, m), 7.68 (1H, d, J = 2.0 Hz), 8.55 ( 1H, s ) .
IR (KBr) v: 2940, 1667 cm 1.
Anal. Calcd. for C33H3,N3O4~0.2H20: C, 72.96; H, 6.94; N, 7.73.
Found C, 72.89; H, 6.91; N, 7.59.
Reference Example 3 In DMF (5m1) was dissolved 7-(3-diethoxyphenyl)-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.25g). To the solution was added, under ice-cooling, thionyl chloride (0.12m1), and the mixture was stirred at room temperature for 30 minutes. Under reduced pressure, the solvent was evaporated, and the residue was suspended in THF (25m1). The solution was added dropwise to a solution of 4-[N-methyl-N-(tetrahydro-2H-pyran-4-yl)aminomethyl]aniline (0.16g) and triethylamine (0.46m1) in THF (4m1), under ice-cooling, and the mixture was stirred under nitrogen atmosphere at room temperature for 5 hours. Under reduced pressure, the solvent was evaporated. To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated to give crude crystals, which were recrystallized from ethyl acetate/diethyl ether to give 7-(3,4-diethoxyphenyl)-1-formyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.26g) as yellow crystals.
mp 145 - 148°C.
1H-NMR (b ppm, CDC13) 1.49 (3H, t, J = 7.0 Hz), 1.50 (3H, t, J = 7.0 Hz), 1.62 - 1.75 (4H, m), 2.21 (3H, s), 2.61 - 2.70 (1H, m) , 3. 04 (2H, t, J = 5. 4 Hz) , 3. 38 (2H, dt, J = 3. 0, 11.2 Hz), 3.58 (2H, s), 3.93 (2H, t, J = 5.4 Hz), 3.95 4.10 (2H, m), 4.10 - 4.24 (4H, m), 6.97 (1H, d, J = 8.8 Hz), 7.11 - 7.21 (3H, m), 7.33 (2H, d, J = 8.4 Hz), 7.49 - 7.59 (4H, m), 7.68 (1H, d, J = 2.0 Hz), 8.55 (1H, s).
IR (KBr) v: 2980, 2944, 1667 cml.
Anal. Calcd. for C35H91N3O5~0.2H20: C, 71.58; H, 7.10; N, 7.15.
Found C, 71.40; H, 7.00: N, 7.22.
Reference Example 4 In DMF (10m1) was dissolved 1- methanesulfonyl-7-(4-morpholinophenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.3g). To the solution was added, under ice-cooling, thionyl chloride (0.15m1), and the mixture was stirred at room temperature for 30 minutes. Under reduced pressure, the solvent was evaporated, and the residue was suspended in THF (50m1). The suspension was added dropwise to a solution of 4-[N-methyl-N-(tetrahydro-2H-pyran-4-yl)aminomethyl]aniline (0.19g) and triethylamine (0.5m1) in THF (5m1), under ice-cooling, and the mixture was stirred under nitrogen atmosphere at room temperature overnight. Under reduced pressure, the solvent was evaporated. To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated to give crude crystals, which were recrystallized from ethyl acetate/ethanol to give 1-methanesulfonyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-7-(4-morpholinophenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.26g) as pale crystals.
mp 239 - 243°C.
1H-NMR (b ppm, CDC13) 1.70 - 1.77 (4H, m), 2.22 (3H, s), 2.60 - 2.70 (1H, m), 2.89 (3H, s), 3.13 (2H, t-like), 3.21 - 3.26 (4H, m), 3.37 (2H, dt, J = 2.6, 11.5 Hz), 3.59 (2H, s), 3.87 - 3.91 (6H, m),4.02 - 4.11 (2H, m), 7.00 (2H, d, J
- 8.8 Hz), 7.34 (2H, d, J = 8.8 Hz), 7.50 - 7.66 (9H, m).
IR (KBr) v: 2951, 2847, 1661, 1609, 1520 ciril.
Anal . Calcd. for C35H42NqO5S ~ 0 . 3H20: C, 66. 08 ~ H, 6. 75; N, 8.81. Found C, 66.06; H, 6.50 N, 8.55.
Reference Examples 5 In DMF (12m1) was suspended 7-(4-exthophenyl)-1-methanesulfonyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.13g). To the suspension was added, under ice-cooling, thionyl chloride (0.04m1) and DMF (catalytic 5 amount), and the mixture was stirred at room temperature for 2 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in THF (15m1).
The solution was added dropwise to a solution of 4-[N-methyl-N-(tetrahydro-2H-pyran-4-yl)aminomethyl]aniline 10 (0.08g) and triethylamine (0.14m1) in THF (5m1), under ice-cooling, and the mixture was stirred under nitrogen atmosphere at room temperature overnight. Under reduced pressure, the solvent was evaporated. To the residue was added water, and the mixture was extracted with ethyl 15 acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated to give crude crystals, which were recrystallized from ethyl acetate/hexane to give 7-(4-ethoxyphenyl)-1-20 methanesulfonyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.16g) as colorless crystals.
mp 184 - 186°C.
1H-NMR (b ppm, CDC13) 1.45 (3H, t, J = 7.0 Hz), 1.64 - 1.75 25 (4H, m), 2.21 (3H, s), 2.61 - 2.72 (1H, m), 2.88 (3H, s), 3.13 (2H, t, J = 5.3 Hz), 3.37 (2H, dt, J = 2.6, 11.2 Hz), 3.59 (2H, s), 3.91 (2H, t, J = 5.3 Hz), 4.01 - 4.07 (2H, m), 4.09 (2H, q, J = 7.0 Hz), 6.98 (2H, d, J = 8.8 Hz), 7.33 (2H, d, J = 8.8 Hz), 7.48 - 7.68 (9H, m).
IR (KBr) v: 2946, 2843, 1661, 1609, 1518, 1495 cm 1.
Anal . Calcd. for C33H39N3~SS ~ C, 67 . 21; H, 6. 67; N, 7 . 13 .
Found C, 67.25 H, 6.33 N, 7.05.
Reference Example 6 In DMF (8m1) was dissolved 1-methoxycarbonyl-7-(4-morpholinophenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.15g). To the solution was added, under ice-cooling, thionyl chloride (0.07m1), and the mixture was stirred at room temperature for 30 minutes.
Under reduced pressure, the solvent was evaporated, and the residue was suspended in THF (25m1). The suspension was added dropwise to a solution of 4-[N-methyl-N-(tetrahydro-2H-pyran-4-yl)aminomethyl]aniline (0.12g) and triethylamine (0.26m1) in THF (5m1), under ice-cooling, and the mixture was stirred under nitrogen atmosphere at room temperature for 4 hours. Under reduced pressure, the solvent was evaporated. To the residue was added water, and the mixture was extracted with ethyl acetate.
The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified with silica gel column chromatography (elution solvent:
methanol/triethylamine/ethyl acetate) to give crude crystals, which were recrystallized from ethyl acetate/hexane to give 1-methoxycarbonyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-7-(4-morpholinophenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.14g) as colorless crystals.
mp 193 - 197°C.
1H-NMR (8 ppm, CDC13) 1.57 - 1.80 (4H, m), 2.21 (3H, s), 2.65 (1H, br), 3.03 (2H, br), 3.20 - 3.23 (4H, m), 3.37 (2H, dt, J = 3.0, 9.9 Hz), 3.58 (2H, s), 3.78 (3H, s), 3.78 (2H, br), 3.87 - 3.92 (4H, m), 4.01 - 4.14 (2H, m), 6.99 (2H, d, J = 9.2 Hz), 7.30 - 7.60 (10H, m).
IR (KBr) v: 2957, 2855, 1701 cm 1.
Anal. Calcd. for C36H92N4O5~0.2H20: C, 70.38; H, 6.96; N, 9.12.
Found C, 70.35; H, 6.81; N, 9.09.
Reference Example 7 In a mixture of water . ethanol . toluene (1 . 1 .
10, v/v, l8.Oml) were dissolved 3,4-diethylphenyl borate (264mg) and 7-bromo-1-methyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide(406mg), and to the solution was added potassium carbonate (162mg). The mixture was stirred under argon atmosphere at room temperature for 30 minutes, and to the mixture was added tetrakistriphenylphosphinepalladium (39mg). The mixture was refluxed under argon atmosphere for 13 hours, diluted with ethyl acetate and washed with water and saturated brine, and the organic layer was dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified with silica gel column chromatography (45g, ethyl acetate .
ethanol = 20 . 1) and recrystallized from ethanol to give 7-(3,4-diethylphenyl)-1-methyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (263mg, 55~) as yellow crystals.
mp 127 - 129°C.
1H-NMR (200 MHz, CDC13) 8 1.47 (3H, t, J = 7.0 Hz), 1.48 (3H, t, J = 7.0 Hz), 1.69 - 1.76 (4H, m), 2.21 (3H, s), 2.53 -2.74 (1H, m), 2.96 (2H, t, J = 4.5 Hz), 3.09 (3H, s), 3.31 - 3.43 (4H, m), 3.57 (2H, s), 4.01 - 4.07 (2H, m), 4.13 (2H, q,J=7.OHz),4.17 (2H,q,J=7.OHz),6.87 (lH,d,J=
8.6 Hz), 6.93 (1H, d, J = 9.0 Hz), 7.07 (1H, dd, J = 6.9, 2.1 Hz), 7.09 (1H, s), 7.30 (2H, d, J = 8.6 Hz), 7.41 -7.42 (2H, m), 7.48 (1H, dd, J = 9.1, 2.3 Hz), 7.54 (2H, d, J = 8.6 Hz), 7.59 (1H, s).
IR (KBr) 1653, 1599, 1514, 1503, 1478, 1406, 1312, 1246, 1188, 1140, 1044 cml.
Anal. Calcd. for C35H43N3O9: C, 73.78; H, 7.61; N, 7.38.

Found C, 73.49: H, 7.54 N, 7.15.
Reference Example 8 In a mixture of THF and ethanol (1 . 1, v/v, 30.0m1) was dissolved ethyl 1-[(4-methylphenyl)sulfonyl]-7-[4-(4 morpholino)phenyl]-2,3-dihydro-1H-1-benzazepine-4 carboxylate (454mg). To the solution was added 1N sodium hydroxide solution (3.0m1), and the mixture was stirred at room temperature for 62 hours. To the mixture was added 1N hydrochloric acid to make the solution weak acidic, and the mixture was extracted with ethyl acetate.
The organic layer was dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 1-[(4-methylphenyl)sulfonyl]-7-[4-(4-morpholino)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid as white crystals. The obtained 1-[(4-methylphenyl)sulfonyl]-7-[4-(4-morpholino)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid was suspended in DMF(l5.Oml). To the suspension was added thionyl chloride (0.15m1), and the mixture was stirred at room temperature for 1 hour. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in dichloromethane (lO.Oml). On the other hand, to 4-[[(N-methyl-N-tetrahydro-2H-pyran-4-yl)amino]methyl]aniline dihydrochloride (296mg) was added dichloromethane (15.0m1), and then was added triethylamine (0.88m1). To ,. CA 02380860 2001-12-03 the obtained mixture was added dropwise at 0°C the previously prepared acid chloride solution, and the mixture was stirred at room temperature for 3 hours. To the mixture was added water, and the separated organic 5 layer was dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was recrystallized from ethanol to give 1-[(4-methylphenyl)sulfonyl]-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-7-[4-(4-10 morpholino)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (359mg, 60~) as white crystals.
mp 258 - 262°C.
1H-NMR (200 MHz, CDC13) 8 1.70 - 1.77 (4H, m), 2.21 (3H, s), 2.35 (3H, s), 2.53 - 2.74 (1H, m), 2.98 (2H, t, J = 5.5 Hz), 15 3.23 (4H, t, J = 4.9 Hz), 3.38 (2H, td, J = 10.4, 3.2 Hz), 3.58 (2H, s), 3.89 (4H, t, J = 4.8 Hz), 3.99 (2H, t, J =
5.4 Hz), 4.01 - 4.09 (2H, m), 6.99 (2H, d, J = 8.8 Hz), 6.97 - 7.06 (2H, m), 7.19 (2H, d, J = 7.6 Hz), 7.29 - 7.34 (2H, m), 7.45 (2H, d, J = 8.6 Hz), 7.53 (2H, d, J = 8.6 Hz), 20 7.50 -7.65 (5H, m).
IR (KBr) 1663, 1609, 1605, 1518, 1495, 1345, 1308, 1233, 1159, 1121, 1090, 928, 816, 733, 671 cml.
Anal. Calcd. for C91H46NQOSS (O.lHzO additive) : C, 69.49; H, 6.57; N, 7.91. Found C, 69.27; H, 6.63: N, 7.92.
25 Reference Example 9 .. CA 02380860 2001-12-03 In DMF (15.0m1) was suspended 1-acetyl-7-[4-(4-morpholino)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (365mg). To the suspension was added thionyl chloride (0.17m1), and the mixture was stirred at room temperature for 1 hour. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in dichloromethane (10.0m1). On the other hand, to 4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]aniline dihydrochloride (327mg) was added dichloromethane (15.0m1), and then was added triethylamine (0.97m1). To the obtained mixture: was added dropwise the previously prepared acid chloride suspension at 0°C, and the mixture was stirred at room temperature for 3 hours. To the mixture was added water, and the separated organic layer was dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified with silica gel column chromatography (50g, ethyl acetate . ethanol = 9 . 1) and washed with hexane/ethyl acetate to give 1-acetyl-N-[4-[[N-metYryl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-7-[4-(4-morpholino)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (116mg, 21%) as pale yellow crystals.
mp 141 - 145°C.
1H-NMR (200 MHz, CDC13) 8 1.65 - 1.87 (4H, m), 2.09 (3H, s), 2.23 (3H, s), 2.61 - 2.78 (1H, m), 2.81 - 3.05 (3H, m), 3.24 (4H, t, J = 4.7 Hz), 3.37 (2H, td, J = 11.4, 2.7 Hz), 3.60 (2H, s), 3.90 (4H, t, J = 4.8 Hz), 4.02 - 4.07 (2H, m), 4.75 - 4.91 (1H, m), 7.23 - 7.27 (1H, m), 7.34 (2H, d, J =
8.4 Hz), 7.52 - 7.69 (8H, m).
IR (KBr) 1657, 1609, 1514, 1497, 1451, 1395, 1314, 1258, 1235 cm 1.
Anal. Calcd. for C36HazN4O4 (1.2H20 additive) : C, 70.15; H, 7.26; N, 9.09. Found C, 69.91; H, 7.05; N, 9.03.
Reference Example 10 In water . ethanol . toluene (1 . 1 . 10, v/v, l8.Oml) were dissolved (4-diethylamino)phenyl borate (234mg) and 7-bromo-1-methyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (391mg). To the solution was added potassium carbonate (268mg), and the mixture was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (37mg), and the mixture was heated to reflux under argon atmosphere for 10 hours. The mixture was diluted with ethyl acetate, and washed with water and saturated brine, and the organic layer was dried with anhydrous magnesium sulfate.
The solvent was evaporated under reduced pressure, and the residue was purified with silica gel column chromatography (45g, ethyl acetate:ethanol=20:1) and recrystallized from ethanol to give 7-(4-diethylaminophenyl)-1-methyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (145mg, 33~) as yellow crystals.
mp 178 - 180°C.
1H NMR (200 MHz, CDC13) 8 1.19 (6H, t, J = 7.0 Hz), 1.64 -1.76 (4H, m), 2.21 (3H, s), 2.54 - 2.72 (1H, m), 2.95 (2H, t, J = 4.5 Hz), 3.07 (3H, s), 3.31 - 3.44 (4H, m), 3.39 (4H, q, J = 7.1 Hz), 3.57 (2H, s), 4.01 - 4.07 (2H, m), 6.74 (2H, d, J = 9.0 Hz), 6.86 (1H, d, J = 8.6 Hz), 7.30 (2H, d, J =
8.4 Hz), 7.41 - 7.59 (8H, m).
IR (KBr) 2948, 1644, 1597, 1514, 1497, 1406, 1312, 1283, 1246, 1188, 1071, 810, 733 cml.
Anal. Calcd. for C35H44NQOz (O.lHzO additive) : C, 75.80; H, 8.03; N, 10.10. Found C, 75.51; H, 7.95; N, 10.10.
Reference Example 11 In water . ethanol . toluene (1 . 1 . 10, v/v, 18.0m1) were dissolved 4-propokyphenyl borate (203mg) and 7-bromo-1-methyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide(455mg). To the solution was added potassium carbonate (312mg), and the mixture was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium .. CA 02380860 2001-12-03 (43mg), and the mixture was heated to reflux under argon atmosphere for 10 hours. The mixture was diluted with ethyl acetate, and washed with water and saturated brine, and the organic layer was dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified with silica gel column chromatography (30g, ethyl acetate . ethanol .
triethyleamine = 100 . 5 . 1) and recrystallized from ethanol/hexane to give 1-methyl-N-(4-[[ N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-7(4-propoxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxamide (349mg, 69~) as yellow crystals.
mp 149 - 151°C.
1H NMR (200 MHz, CDC13) 8 1.05 (3H, t, J = 7.4 Hz), 1.63 -1.76 (4H, m), 1.83 (2H, sextet, J = 7.2 Hz), 2.20 (3H, s), 2.53 - 2.73 (1H, m), 2.95 (2H, t, J = 4.5 Hz), 3.07 (3H, s), 3.31 - 3.43 (4H, m), 3.56 (2H, s), 3.96 (2H, t, J = 6.6 Hz), 4.01 - 4.07 (2H, m), 6.87 (1H, d, J = 8.4 Hz), 6.95 (2H, d, J = 8.8 Hz), 7.29 (2H, d, J = 8.6 Hz), 7.39 (1H, s), 7.43 (1H, dd, J = 8.6, 2.2 Hz), 7.47 (2H, d, J = 8.6 Hz), 1H (d) was concealed under 7.49, 7.54 (2H, d, J = 8.6 Hz), 7.62 (1H, s) .
IR (KBr) 2946, 1651, 1607, 1514, 1505, 1312, 1242, 1182, 814 cm 1.
Anal. Calcd. for C34HQ1N3O3 (0.1H20 additive) : C, 75.41; H, ". CA 02380860 2001-12-03 7.67; N, 7.76. Found C, 75.30; H, 7.75; N, 7.82.
Reference Example 12 In DMF (lO.Oml) was suspended 1-formyl-7-(4-propoxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (433mg). To the suspension was added thionyl chloride (0.22m1), and the mixture was stirred at room temperature for 30 minutes. Under reduced pressure, the solvent was evaporated, and to the mixture was added THF
(15.0m1). On the other hand, to 4-[[N-methyl-N-' tetrahydro-2H-pyran-4-yl)amino]methyl]aniline dihydrochloride (434mg) was added THF (10.0m1) and then added triethylamine (1.29m1). The previously prepared acid chloride suspension was added dropwise at 0°C. The mixture was stirred at room temperature for 4 hours. To the mixture was added water, and the mixture was washed with water and saturated brine, and the organic layer was dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was recrystallized from ethanol to give 1-formyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-7-(4-propoxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxamide (554mg, 81s) as white crystals.
mp 207 - 209°C.
1H NMR (200 MHz, CDC13) 8 1.06 (3H, t, J = 7.4 Hz), 1.63 -1.77 (4H, m), 1.85 (2H, sextet, J = 7.0 Hz), 2.21 (3H, s), 2.57 - 2.72 (1H, m), 3.04 (2H, t, J = 4.8 Hz), 3.37 (2H, td, J = 11.4, 3.1 Hz), 3.57 (2H, s), 3.90 - 4.08 (6H, m), 7.00 (2H, d, J = 9.0 Hz), 7.20 (1H, d, J = 8.2 Hz), 7.32 (2H, d, J = 8.4 Hz), 7.47 - 7.54 (6H, m), 7.57 (1H, dd, J = 8.0, 2.2 Hz), 7.68 (1H, d, J = 2.0 Hz), 8.56 (1H, s).
IR (KBr) 1669, 1609, 1522, 1497, 1360, 1314, 1252 cml.
Anal. Calcd. for C34H39N3O9: C, 73.75; H, 7.10; N, 7.59.
Found C, 73.48; H, 7.11; N, 7.50.
Reference Example 13 In THF (10.0m1) and catalytic amount of DMF was suspended 1-methylsulfonyl-7-(4-propoxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (236mg). To the suspension was added oxalyl chloride (0.13m1), and the mixture was stirred at room temperature for 1 hour.
Under reduced pressure, the solvent was evaporated. To the residue was added THF (10.0m1). On the other hand, to 4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]aniline dihydrochloride (207mg) was added THF (10.0m1), and then was added triethylamine (0.61m1).
To the obtained mixture was added dropwise at 0°C the previously prepared acid chloride suspension, and the mixture was stirred at room temperature for 3.5 hours.
To the mixture was added ethyl acetate, and the mixture was washed with water, 1N sodium hydroxide solution, water and saturated brine. The organic layer was dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified with silica gel column chromatography (10g, ethyl acetate . ethanol . triethylamine = 100 . 10 . 1) and recrystallized from ethanol to give 1-methylsulfonyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-7-(4-propoxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxamide(205mg, 58~) as white crystals.
mp 199 - 202°C.
1H NMR (200 MHz, CDC13) 8 1.06 (3H, t, J = 7.4 Hz), 1.63 -1.79 (4H, m), 1.85 (2H, sextet, J = 7.0 Hz), 2.21 (3H, s), 2.54 - 2.74 (1H, m), 2.98 (3H, s), 3.14 (2H, t, J = 5.2 Hz), 3.38 (2H, td, J = 11.3, 3.2 Hz), 3.58 (2H, s), 3.89 - 4.07 (6H, m), 6.96 - 7.03 (2H, m), 7.33 (2H, d, J = 8.4 Hz), 7.47 - 7.67 (9H, m).
IR (KBr) 1653, 1609, 1518, 1493, 1341, 1314, 1248, 1154 cm Anal. Calcd. for C34H91N3OSS: C, 67.64: H, 6.84; N, 6.96.
Found C, 67.37; H, 6.77; N, 6.89.
Reference Example 14 In THF (lO.Oml) and catalytic amount of DMF was suspended 7-(4-ethoxy-3-fluorophenyl)-1-methylsulfonyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (182mg).
To the suspension was added oxalyl chloride(0.12m1), and the mixture was stirred at room temperature for I hour.
Under reduced pressure, the solvent was evaporated, and to the residue was added THF (10.0m1). On the other hand, to 4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]
aniline dihydrochloride (158mg) was added THF (10.0m1), and then was added triethylamine (0.47m1). To the obtained mixture was added dropwise at 0°C the previously prepared acid chloride suspension, and the mixture was stirred at room temperature for 3 hours. To the mixture was added ethyl acetate, and the mixture was washed with water, N sodium hydroxide solution, water and saturated brine. The organic layer was dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified with silica gel column chromatography (15g, ethyl acetate ethyl acetate . ethanol . triethylamine = 100 . 10 . 1), and recrystallized from ethanol to give 7-(4-ethoxy-3-fluorophenyl)-1-methylsulfonyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (140mg, 51$) as white crystals.
mp 199 - 202°C.
1H NMR (200 MHz, CDC13) 8 1.49 (3H, t, J = 7.0 Hz), 1.64 -1.77 (4H, m), 2.21 (3H, s), 2.57 - 2.70 (1H, m), 2.89 (3H, s), 3.14 (2H, t, J = 5.4 Hz), 3.38 (2H, td, J = 11.3, 2.9 Hz), 3.57 (2H, s, 3.91 (2H, t, J = 5.7 Hz), 4.02 - 4.07 (2H, m) , 4 . 17 ( 2H, q, J = 6 . 9 Hz ) , 7 . 04 ( 1H, t, J = 8 . 8 Hz ) , 7.28 - 7.35 (3H, m), 7.48 - 7.61 (7H, m), 7.65 (1H, d, J =
8.4 Hz) .
IR (KBr) 1661, 1522, 1497, 1343, 1310, 1269, 1238, 1154, 1138 cm 1.
Anal. Calcd. for C33H3BFN3OSS (0.3H20 additive) ] C, 64. 64; H, 6.35: N, 6.85. Found C, 64.46 H, 6.41 N, 6.80.
Reference Example 15 In DMF (5.5m1) was dissolved 7-(4-ethoxy-3-fluorophenyl)-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (398mg). To the solution was added thionyl chloride (0.20m1), and the mixture was stirred at room temperature for 30 minutes. Under reduced pressure, the solvent was evaporated, and to the residue was added THF (10.0m1). On the other hand, to 4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]aniline dihydrochloride (394mg) was added THF (10.0m1), and then was added triethylamine (1.17 ml). To the obtained mixture was added dropwise at 0°C the previously prepared acid chloride suspension, and the mixture was stirred at room temperature for 4 hours. To the mixture was added ethyl acetate, and the mixture was washed with water, 1N
sodium hydroxide solution, water and saturated brine.
The organic layer was dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was recrystallized from ethanol to give 7-(4-ethoxy-3-fluorophenyl)-1-formyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (453mg, 73%) as white crystals.
mp 193 - 196°C.
1H NMR (200 MHz, CDC1-3) 8 1. 49 (3H, t, J = 7.0 Hz) , 1. 64 -1.75 (4H, m), 2.21 (3H, s), 2.58 - 2.74 (1H, m), 3.04 (2H, t, J = 5.0 Hz), 3.37 (2H, td, J = 11.3, 3.1 Hz), 3.58 (2H, s), 3.92 (2H, t, J = 5.3 Hz), 4.02 - 4.07 (2H, m), 4.17 (2H, q, J = 7.1 Hz), 7.05 (1H, t, J = 8.6 Hz), 7.20 (1H, d, J =
8.4 Hz), 7.29 - 7.37 (5H, m), 7.45 (1H, s), 7.54 (2H, d, J
- 8.4 Hz), 7.56 (1H, s), 7.66 (1H, d, J = 2.0 Hz), 8.55 (1H, s) .
IR (KBr) 1667, 1514, 1501, 1360, 1314, 1269, 1238 cml.
Anal. Calcd. for C33H36FN304 (0.1H20 additive) : C, 70.85; H, 6.52; N, 7.51. Found C, 70.55; H, 6.54; N, 7.45.
Reference Example 16 A solution of methyl 5-bromo-N-tosylanthranylate (200g) in DMF (450m1) was added dropwise, under ice-cooling, to a suspension of 60% sodium hydride (25g) in DMF (50m1). Under nitrogen atmosphere, the mixture was stirred at room temperature for 2 hours, and to the mixture were added sodium iodide (78g) and ethyl 4-bromobutyrate (82m1). The mixture was stirred under nitrogen atmosphere at 85°C for 24 hours, and to the mixture was added potassium t-butoxide (70g) under ice-cooling. The mixture was stirred at 85°C for 1.5 hours, and the solvent was evaporated. To the residue was added ice-water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated to give ethyl (methyl) 7-bromo-5-hydroxy-1-tosyl-2,3-dihydro-1H-1-benzazepine-4-Garb oxylate (mixture) (153g) as white crystals.
1H NMR (8 ppm, CDC13) 1. 31 (1. 5H, t, J = 7. 1 Hz) , 2.29 (2H, t, J = 6.4 Hz) , 2.40 (3H, s) , 3.72 (1. 5H, s) , 4.08 (2H, t, J = 6.4 Hz), 4.17 (1H, q, J = 7.1 Hz), 7.17 (2H, d, J = 8.2 Hz), 7.38 (2H, d, J = 8.0 Hz), 7.41 - 7.46 (1H, m), 7.60 -7.66 (2H, m), 11.83 (0.5H, s), 11.91 (0.5H, s).
Reference Example 17 To ethyl (methyl) 7-bromo-5-hydroxy-1-tosyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (mixture) (32.4g) were added acetic acid (200m1) and concentrated sulfuric acid (120m1), and the mixture was stirred at 80°C for 2.5 hours. The mixture was poured into ice-water, and the mixture was neutralized with sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified with silica gel column chromatography (hexane/ethyl acetate) to give 7-bromo-1,2,3,4-tetrahydro-1-benzazepin-5-one (8.55g) as pale yellow crystals.
mp 99 - 101°C.
1H NMR (8 ppm, CDC13) 2. 18 (2H, quint, J = 7. 1 Hz) , 2. 82 (2H, t, J = 7.2 Hz), 3.25 (2H, t, J = 6.6 Hz), 4.65 (1H, br), 6.65 (1H, d, J = 8.6 Hz), 7.20 (1H, dd, J = 2.2, 8.6 Hz), 7.82 (1H, d, J = 2.2 Hz).
IR (KBr) v: 3364, 2955, 1661 cm 1.
Reference Example 18 In THF (200m1) were dissolved 7-bromo-1,2,3,4-tetrahydro-1-benzazepin-5-one (7g) and dimethylaminopyridine (22g). To the solution was added di-t-butyl dicarbonate (60g), and the mixture was refluxed for 1.5 hours. The solvent was evaporated. To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1M citric acid solution, water and saturated brine, and dried with anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give a mixture of 7-bromo-1-(t-butoxycarbonyl)-1,2,3,4-tetrahydro-1-benzazepin-5-one and 7-bromo-1-(t-butoxycarbonyl)-5-(t-butoxycarbonyloxy)-2,3-dihydro-1H-1-benzazepine (24.6g) as yellow oil.
1H NMR (8 ppm, CDC13) 1.43 (4.5H, s), 1.49 (9H, s), 2.15 (1H, quint, J = 6.8 Hz), 2.76 (2H, t, J = 6.8 Hz), 3.73 (2H, t, J = 6.8 Hz), 5.97 (0.5H, t, J = 4.6 Hz), 7.17 (0.5H, br), 7.35 (1H, br), ?.54 - 7.59 (1H, m), 7.98 (0.5H, d, J = 2.6 Hz) .
Reference Example 19 In dimethyl carbonate (400m1) was dissolved a mixture (3.3g) of 7-bromo-1-(t-butoxycarbonyl)-1,2,3,4-tetrahydro-1-benzazepin-5-one and 7-bromo-1-(t-butoxycarbonyl)-5-(t-butoxycarbonyloxy)-2,3-dihydro-1H-1-benzazepine. To the solution was added sodium methoxide (23.0g), and the mixture was refluxed under nitrogen atmosphere for 2.5 hours and poured into ice-water. To the mixture was added 1M citric acid solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give methyl 7-bromo-1-(t-butoxycarbonyl)-1,2,3,4-tetrahydro-1-benzazepin-5-one-4-carboxylate (23.8g) as yellow oil.
1H NMR (8 ppm, CDC13) 1.36 (4.5H, s), 1.52 (4.5H, s, 2.43 -2.55 (2H, m), 3.39 - 3.54 (0.5H, m), 3.72 (1.5H, s), 3.84 (1.5H, s), 3.89 - 4.04 (2H, m), 7.12 (0.5H, br), 7.42 (0.5H, br), 7.51 (0.5H, dd, J = 2.2, 8.4 Hz), 7.58 (0.5H, dd, J =
2.4, 8.6 Hz), 7.82 (0.5H, d, J = 2.2 Hz), 8.00 (0.5H, d, J
- 2.2 Hz) .
Reference Example 20 In THF (150m1) was dissolved methyl 7-bromo-1-(t-butoxycarbonyl)-1,2,3,4-tetrahydro-1-benzazepin-5-one-4-carboxylate (7.2g). To the solution was added sodium borohydride (0.7g) at -40°C, and then was added dropwise methanol (15m1). The mixture was stirred at -15°C for 1 hour. To the mixture was added 1M citric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated. The residue was dissolved in THF (150m1), and to the solution was added triethylamine (7.5m1). To the mixture was added dropwise, under ice-cooling, methanesulfonyl chloride (2.1m1). Under nitrogen atmosphere, the mixture was stirred at room temperature for 1.5 hours, and to the mixture was added dropwise DBU
(13.5m1) at room temperature. The mixture was stirred at 90°C for 10 minutes, and the solvent was evaporated. To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give methyl 7-bromo-1-(t-butoxycarbonyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (5.18g) as colorless crystals.
mp 144 - 145°C.
1H NMR (8 ppm, CDC13) 1.47 (9H, s) , 2. 89 (2H, t, J = 4.8 Hz) , 3.61 (2H, br), 3.83 (3H, s), 7.27 (1H, br), 7.39 (1H, dd, J
- 1.8, 8.4 Hz), 7.54 - 7.55 (2H, m).
IR (KBr) v: 2978, 1709 cml.
Anal. Calcd. for Cl~HZOBrN04: C, 53.42; H, 5.27; N, 3.66.
Found C, 53.58; H, 5.12; N, 3.52.
Reference Example 21 In ethyl acetate (50m1) was dissolved methyl 7-bromo-1-(t-butoxycarbonyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate(1.5g). To the solution was added 6N
hydrochloric acid (2m1), and the mixture was heated to stir at 80°C for 2 hours, neutralized with 1N sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated to give methyl 7-bromo-2,3-dihydro-1H-1-benzazepine-4-carboxylate (1.0g) as yellow crystals.
mp 143 - 145°C.

1H NMR (8 ppm, CDC13) 2. 85 (2H, t, J = 4.8 Hz) , 3. 35 (2H, t, J = 4.8 Hz), 3.80 (3H, s), 4.62 (1H, br), 6.49 (1H, d, J =
8.4 Hz), 7.15 (1H, dd, J = 2.4, 8.4 Hz), 7.37 (1H, d, J =
2.4 Hz), 7.53 (1H, s).
IR (KBr) v: 3384, 2949, 1694 cml.
Anal. Calcd. for C12H12BrNOZ: C, 51.09; H, 4.29; N, 4.96.
Found C, 51.17; H, 4.32; N, 4.97.
Reference Example 22 To anhydrous acetic acid (0.84m1) was added dropwise formic acid (0.4m1), under ice-cooling, and the mixture was stirred, under nitrogen atmosphere, at 50°C for 2 hours. To the mixture was added THF (5m1), and to the mixture was added dropwise, under ice-cooling, a solution of methyl 7-bromo-2,3-dihydro-1H-1-benzazepine-4-carboxy late (1.0g) in THF (15m1). The mixture was stirred at room temperature overnight. The solvent was evaporated, and to the residue was added water. The mixture was extracted with ethyl acetate. The organic layer was washed with sodium hydrogen carbonate solution, water an saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated to give methyl 7-bromo-1-formyl -2,3-dihydro-1H-1-benzazepine-4-carboxylate (1.07g) as colorless crystals.
mp 175 - 176°C.
1H NMR (8 ppm, CDC13) 2.93 (2H, t, J = 5.3 Hz), 3.80 (2H, t, J = 5.3 Hz), 3.83 (3H, s), 7.01 (1H, d J = 8.5 Hz), 7.50 (1H, dd, J = 2.2, 8.5 Hz), 7.58 (1H, s), 7.65 (1H, d, J =
2.2 Hz), 8.46 (1H, s).
IR (KBr) v: 2951, 1713, 1680 cm 1.
Anal. Calcd. for C13H1zBrN03: C, 50.34; H, 3.90; N, 4.52.
Found C, 50.43 H, 3.75: N, 4.45.
Reference Example 23 To a mixture of methyl 7-bromo-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (3.51g), 4-morpholinophenyl borate (3.51g) and potassium carbonate (3.75g) was added a mixture of water (20m1), ethanol (20m1) and toluene (100m1), and the mixture was stirred under argon atmosphere at room temperature for 40 minutes.
To the mixture was added tetrakis(triphenylphosphine)-palladium (0.52g), and the mixture was refluxed under argon atmosphere for 12 hours and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give methyl 1-formyl-7-(4-morpholinophenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (3.64g) as pale yellow crystals.
mp 178 - 181°C.
1H NMR (8 ppm, CDC13) 2.95 (2H, t, J = 5.1 Hz), 3.23 (4H, t, J = 4.9 Hz), 3.82 - 3.92 (6H, m), 3.84 (3H, s), 6.97 - 7.04 (2H, m), 7.17 (1H, d, J = 8.2 Hz), 7.45 - 7.60 (3H, m), 7.69 (1H, d, J = 2.2 Hz), 7.76 (1H, s), 8.53 (1H, s).
IR (KBr) v: 2951, 2830, 1709, 1674 cml.
Reference Example 24 In methanol (250m1) and THF (250m1) was dissolved methyl 1-formyl-7-(4-morpholinophenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (3.54g). To the solution was added 1N sodium hydroxide solution (90m1), and the mixture was stirred at room temperature overnight and concentrated. To the mixture was added water, and the mixture was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate, and the solvent was evaporated to give 1-formyl-7-(4-morpholinophenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (3.30g) as colorless crystals.
mp 247 - 257°C (dec.).
1H NMR (8 ppm, DMSO-d6) 2.75 (2H, t-like) 3.14 - 3.19 (4H, m), 3.70 - 3.78 (6H, m), 7.03 (2H, d, J = 8.8 Hz), 7.36 (1H, d, J = 8.4 Hz), 7.62 - 7.71 (4H, m), 7.87 (1H, s), 8.51 (1H, s) .
IR (KBr) v: 1671 cml.
Anal. Calcd. for CZZH22N204'0.7Hz0: C, 67.57; H, 6.03; N, 7.16.
Found C, 67.48; H, 5.74; N, 6.98.

Reference Example 25 A mixture of methyl 7-bromo-1-(t-butoxycarbonyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (2.0g), 4-morpholinophenyl borate (1.2g), and 1M potassium carbonate solution (15m1), ethanol (15m1) and toluene (100m1) was stirred under argon atmosphere at room temperature for 20 minutes. To the mixture was added tetrakis(triphenylphosphine)palladium (0.24g), and the mixture was refluxed under argon atmosphere for 12 hours and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give methyl 1-(t-butoxycarbonyl)-7-(4-morpholinophenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (3.64g) as pale yellow crystals.
mp 183 - 185°C.
1H-NMR (8 ppm, CDC13) 1.49 (9H, s) , 2. 90 (2H, t, J = 5.0 Hz) , 3.19 - 3.24 (4H, m), 3.69 (2H, br), 3.83 (3H, s), 3.87 3.91 (4H, m), 6.98 (2H, d, J = 9.0 Hz), 7.48 (2H, br), 7.52 (2H, d, J = 9.0 Hz), 7.58 (1H, s), 7.73 (1H, s).
IR (KBr) v: 2973, 1705 cm 1.
Anal. Calcd. for C27H32NzO5: C, 69.81 H, 6.94; N, 6.03.
Found C, 69.57; H, 6.76 N, 5.76.

Reference Example 26 In ethyl acetate (100m1) was dissolved methyl 1-(t-butoxycarbonyl)-7-(4-morpholinophenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (2.0g). To the solution was added 6N hydrochloric acid (40m1), and the mixture was stirred at 80°C for 30 minutes, neutralized with 1N
sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated to give 7-(4-morpholinophenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (1.46g) as yellow crystals.
mp 175 - 182°C (dec.).
1H-NMR (8 ppm, CDC13) 2. 89 (2H, t, J = 4.5 Hz) , 3.17 - 3.22 (4H, m), 3.41 (2H, t, J - 4.5 Hz), 3.81 (3H, s), 3.87 -3.91 (4H, m), 6.67 (1H, d, J = 8.3 Hz), 6.97 (2H, d, J =
8 . 8 Hz ) , 7 . 33 ( 1H, dd, J = 2 . 0, 8 . 3 Hz ) , 7 . 45 - 7 . 50 ( 3H, m), 7.73 (1H, s).
IR (KBr) v: 3378, 2953, 1694 cm 1.
Anal. Calcd. for CZZHZ9N203~0.2Hz0: C, 71.80: H, 6.68 N, 7.61.
Found C, 71.51; H, 6.72; N, 7.47.
Reference Example 27 To anhydrous acetic acid (0.2m1) was added dropwise formic acid (0.1m1), under ice-cooling, and the mixture was heated to stir under nitrogen atmosphere at 50°C for 2 hours. To the mixture was added THF (5m1), and then to the mixture was added dropwise, under ice-cooling, a solution of methyl 7-(4-morpholinophenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.3g) in THF (15m1). The mixture was stirred at room temperature for 1.5 hours.
The solvent was evaporated, and to the residue was added water. The mixture was extracted with ethyl acetate.
The organic layer was washed with sodium hydrogen carbonate solution, water and saturated brine, and dried with anhydrous magnesium sulfate, and the solvent was evaporated to give methyl 1-formyl-7-(4-morpholinophenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.3g) as pale yellow crystals.
Reference Example 28 A mixture of methyl 7-bromo-1-(t-butoxycarbonyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (1.0g), 4-ethoxyphenyl borate (0.5g), 1M potassium carbonate solution (8m1), ethanol (8m1) and toluene (50m1) was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakis(triphenylphosphine)palladium (0.12g), and the mixture was refluxed overnight under argon atmosphere and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give methyl 1-(t-butoxycarbonyl)-7-(4-morpholinophenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (1.1g) as colorless crystals.
1H-NMR (8 ppm, CDC13) 1.38 - 1. 49 (12H, m) , 2. 91 (2H, t, J =
5. 3 Hz) , 3. 68 (2H, br) , 3. 83 (3H, s) , 4 . 09 (2H, q, J = 7. 0 Hz), 6.97 (2H, d, J = 8.8 Hz), 7.47 - 7.55 (4H, m), 7.58 (1H, s), 7.74 (1H, 4).
IR (KBr) v: 2980, 1705 cml.
Reference Example 29 In ethyl acetate (50m1) was dissolved methyl 1-(t-butoxycarbonyl)-7-(4-ethoxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (1.1g). To the solution was added 6N hydrochloric acid (10m1) and the mixture was stirred at 80°C for 40 minutes, neutralized with 1N
sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated to give methyl 7-(4-ethoxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.78g) as yellow crystals.
mp 157 - 158°C.
1H-NMR (b ppm, CDC13) 1.43 (3H, t, J = 7.0 Hz) , 2.88 (2H, t, J = 4.6 Hz), 3.40 (2H, t, J = 4.6 Hz), 3.81 (3H, s), 4.07 (2H, q, J = 7. 0 Hz) , 6. 66 (1H, d, J = 8. 3 Hz) , 6. 94 (2H, d, J = 9.2 Hz), 7.31 (1H, dd, J = 2.2, 8.3 Hz), 7.41 - 7.47 (3H, m), 7.73 (1H, s).
IR (KBr) v: 3380, 2980, 2948, 1699 cml.
Reference Example 30 To anhydrous acetic acid (0.18m1) was added dropwise formic acid (0.09m1) under ice-cooling, and the mixture was stirred under nitrogen atmosphere at 50°C for 2 hours.
To the mixture was added THF (2m1) and then was added dropwise, under ice-cooling a solution of methyl 7-(4-ethoxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.25g) in THF (15m1), and the mixture was stirred at room temperature for 4 hours. The solvent was evaporated, and to the residue was added water. The mixture was extracted with ethyl acetate. The organic layer was washed with sodium hydrogen carbonate solution, water and saturated brine, and dried with anhydrous magnesium.
sulfate, and the solvent was evaporated to give methyl 7-(4-ethoxyphenyl)-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.24g) as yellow crystals.
mp 133 - 135°C.
1H-NMR (8 ppm, CDC13) 1.45 (3H, t, J = 6.9 Hz), 2.95 (2H, t, J = 4.9 Hz), 3.82 - 3.88 (5H, m), 4.09 (2H, q, J = 6.9 Hz), 6.99 2H, d, J = 8.8 Hz), 7.17 (1H, d, J = 8.0 Hz), 7.49 -7.58 (3H, m) , 7. 68 (1H, d, J = 2.2 Hz) , 7.75 (1H, s) , 8.53 (1H, s) .
IR (KBr) v: 2980, 2948, 1709, 1678 cml.
Reference Example 31 In methanol (25m1) and THF (30m1) was dissolved methyl 7-(4-ethoxyphenyl)-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.24g). To the solution was added 1N sodium hydroxide solution (5m1) and the mixture was stirred at room temperature overnight and concentrated. To the residue was added water, and the mixture was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated to give 7-(4-ethoxyphenyl)-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.23g) as pale yellow crystals.
mp 224 - 226°C.
1H-NMR (8 ppm, CDC13 ) 1. 4 6 ( 3H, t, J = 6 . 9 Hz ) , 2 . 97 ( 2H, t, J = 5.1 Hz), 3.88 (2H, t, J = 5.1 Hz), 4.10 (2H, q, J = 6.9 Hz), 7.00 (2H, d, J = 8.8 Hz), 7.20 (1H, d, J = 8.1 Hz), 7.53 (2H, d, J = 8.8 Hz), 7.59 (1H, dd, J = 2.0, 8.1 Hz), 7.70 (1H, d, J = 2.0 Hz), 7.86 (1H, s), 8.56 (1H, s).
IR (KBr) v: 2982, 1669, 1682 cm 1.
Anal. Calcd. for CzoH19N04~0.4Hz0: C, 69.71; H, 5.79; N, 4.06.
Found C, 69.80: H, 6.00: N, 3.80.

Reference Example 32 A mixture of methyl 7-bromo-1-(t-butoxycarbonyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (1.0g), 4-(2-ethoxyethoxy)phenyl borate (0.6g), 1M potassium carbonate solution (8m1), ethanol (8m1) and toluene (50m1) was stirred under argon atmosphere at room temperature for 20 minutes. To the mixture was added tetrakis(triphenylphosphine)palladium (0.12g), and the mixture was refluxed overnight under argon atmosphere and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give methyl 1-(t-butoxycarbonyl)-7-[4-(2-ethoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (1.1g) as colorless oil.
1H-NMR (8 ppm, CDC13) 1.26 (3H, t, J = 7.1 Hz), 1.49 (9H, s), 2.91 (2H, t, J = 4.8 Hz), 3.63 (2H, q, J - 7.1 Hz), 3.68 (2H, br), 3.83 (2H, t, J = 4.9 Hz), 3.83 (3H, s), 4.17 (2H, t, J = 4. 9 Hz) , 7.00 (2H, d, J = 8. 8 Hz) , 7.47 - 7. 53 (4H, m), 7.58 (1H, s), 7.73 (1H, s).
IR (neat) v: 2976, 1705 cml.
Reference Example 33 In ethyl acetate (50m1) was dissolved methyl 1-(t-butoxycarbonyl)-7-[4-(2-ethoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (1.1g). To the solution was added 6N hydrochloric acid (20m1), and the mixture was stirred at 80°C for 45 minutes, neutralized with 1N
sodium hydroxide solution and was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated to give methyl 7-[4-(2-ethoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.7g) as yellow crystals.
mp 102 - 108°C.
1H-NMR (8 ppm, CDC13) 1.26 (3H, t, J = 7.0 Hz) , 2.88 (2H, t, J = 4.7 Hz), 3.40 (2H, t, J = 4.7 Hz), 3.62 (2H, q, J = 7.0 Hz), 3.81 (3H, s), 3.82 (2H, t, J = 5.0 Hz), 4.16 (2H, t, J
- 5 . 0 Hz ) , 6 . 67 ( 1H, d, J = 8 . 5 Hz ) , 6 . 97 ( 2H, d, J = 8 . 8 Hz) , 7.31 (1H, dd, J = 2.2, 8.5 Hz) , 7.42 - 7.47 (3H, m) , 7.73 (1H, s).
IR (KBr) v: 3370, 2976, 2946, 2870, 1698 crril.
Anal. Calcd. for CZZH2sNO9: C, 71.91; H, 6.86; N, 3.81. Found C, 71.88; H, 6.79; N, 3.78.
Reference Example 34 To anhydrous acetic acid (0.25m1) was added formic acid (0.13m1) under ice-cooling, and the mixture was stirred under nitrogen atmosphere at 50°C for 2 hours.
To the mixture was added THF (2m1) and then was added dropwise, under ice-cooling, a solution of methyl 7-[4-(2-ethoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.25g) in THF (lOml), and the mixture was stirred at room temperature overnight. The solvent was evaporated, and to the residue was added water. The mixture was extracted with ethyl acetate. The organic layer was washed with sodium hydrogen carbonate solution, water and saturated brine, and dried with anhydrous magnesium sulfate, and the solvent was evaporated to give methyl 7-[4-(2-ethoxyethoxy)phenyl]-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.2g) as colorless crystals.
mp 138 - 142°C.
1H-NMR (b ppm, CDC13) 1.27 (3H, t, J = 6. 9 Hz) , 2. 95 (2H, t, J = 5.1 Hz), 3.63 (2H, q, J = 6.9 Hz), 3.81 - 3.88 (7H, m), 4.19 (2H, t, J = 5.0 Hz), 7.03 (2H, d, J = 8.8 Hz), 7.17 (1H, d, J = 8.2 Hz) , 7.48 - 7.59 (3H, m) , 7. 68 (1H, d, J =
2.2 Hz), 7.75 (1H, s).
IR (KBr) v: 2872, 1709, 1678 cml.
Anal. Calcd. for C23Hz5N05: C, 69.86; H, 6.37; N, 3.54. Found C, 69.88; H, 6.43; N, 3.49.
Reference Example 35 In methanol (25m1) and THF (25m1) was dissolved methyl 7-[4-(2-ethoxyethoxy)phenyl]-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.2g). To the solution was added 1N sodium hydroxide solution (5m1), and the mixture was stirred at room temperature overnight and concentrated. To the residue was added water, and the mixture was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated to give 7-[4-(2-ethoxyethoxy)phenyl]-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.19g) as colorless crystals.
mp 190 - 192°C.
1H-NMR (8 ppm, CDC13) 1.27 (3H, t, J = 7.0 Hz) , 2. 97 (2H, t, J = 4.4 Hz), 3.64 (2H, q, J = 7.0 Hz), 3.81 - 3.90 (4H, m), 4.19 (2H, t, J = 5.0 Hz), 7.03 (2H, d, J = 8.8 Hz), 7.19 (1H, d, J = 8.2 Hz), 7.52 (2H, d, J = 8.8 Hz), 7.59 (1H, dd, J = 2.2, 8.2 Hz) , 7. 69 (1H, d, J = 2.2 Hz) , 7.85 (1H, s) , 8.55 (1H, s) .
IR (KBr) v: 2936, 2872, 1682, 1671 cml.
Anal. Calcd. for C22H23N05: C, 69.28; H, 6.08; N, 3.67. Found C, 69.00; H, 6.31; N, 3.56.
Reference Example 36 A mixture of methyl 7-bromo-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (20g), 4-(2-ethoxyethoxy)phenyl borate (14.9g), 1M potassium carbonate solution (130m1), ethanol (130m1) and toluene (1000m1) was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakis(triphenylphosphine)palladium (3g), and the mixture was refluxed under argon atmosphere for 15 hours and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give methyl 7-[4-(2-ethoxyethoxy)phenyl]-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (25.2g) as colorless crystals.
Reference Example 37 A mixture of methyl 7-bromo-1-(t-butoxycarbonyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (1.0g), 4-(3-ethoxypropoxy)phenyl borate (0.62g), 1M potassium carbonate solution (8m1), ethanol (8m1) and toluene (50m1) was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakis(triphenylphosphine)palladium (0.12g), and the mixture was refluxed overnight under argon atmosphere and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give methyl 1-(t-butoxycarbonyl)-7-[4-(3-ethoxyPropoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (1.2g) as colorless crystals.
mp 125 - 128°C.
1H-NMR (8 ppm, CDC13 ) 1. 21 ( 3H, t, J = 7 . 0 Hz ) , 1. 4 9 ( 9H, s ) , 2.02 - 2.14 (2H, m), 2.91 (2H, t, J = 4.2 Hz), 3.51 (2H, q, J = 7.0 Hz) , 3. 62 (2H, t, J = 6.3 Hz) , 3. 65 (2H, br) , 3. 83 (3H, s), 4.12 (2H, t, J = 6.2 Hz), 6.98 (2H, d, J = 8.8 Hz), 7.40 - 7.55 (4H, m), 7.57 (1H, s), 7.73 (1H, s).
IR (KBr) v: 2976, 2948, 2872, 1705 cml.
Reference Example 38 In ethyl acetate (50m1) was dissolved methyl 1-(t-butoxycarbonyl)-7-[4-(3-ethoxypropoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (1.2g). To the solution was added 6N hydrochloric acid (lOml), and the mixture was stirred at 80°C for 30 minutes, neutralized with 1N sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated to give methyl 7-[4-(3-ethoxypropoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.8g) as yellow crystals.
mp 99 - 102°C.
1H-NMR (S ppm, CDC13) 1.21 (3H, t, J = 7.0 Hz) , 2. 0l - 2.13 (2H, m), 2.88 (2H, t, J = 4.7 Hz), 3.41 (2H, t, J = 4.7 Hz), 3.51 (2H, q, J = 7.0 Hz), 3.62 (2H, t, J = 6.2 Hz), 3.81 (3H, s) , 4. 10 (2H, t, J = 6.2 Hz) , 4. 78 (1H, br) , 6. 67 (1H, d, J = 8 . 5 Hz ) , 6 . 95 ( 2H, d, J = 8 . 8 Hz ) , 7 . 32 ( 1H, dd, J =
2.2, 8.5 Hz), 7.43 - 7.47 (3H, m), 7.73 (1H, s).
IR (KBr) v: 3374, 2949, 2868, 1699 cml.
Anal. Calcd. for C23HZ~N04: C, 72.42; H, 7.13 N, 3.67. Found C, 72.24; H, 7.04; N, 3.67.
Reference Example 39 To anhydrous acetic acid (0.22m1) was added dropwise formic acid (O.llml) under ice-cooling, and the mixture was stirred under nitrogen atmosphere at 50°C for 2 hours.
To the mixture was added THF (2m1) and then was added dropwise, under ice-cooling, a solution of methyl 7-[4-(3-ethoxypropoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.35g) in THF (15m1), and the mixture was stirred at room temperature overnight. The solvent was evaporated, and to the residue was added water. The mixture was extracted with ethyl acetate. The organic layer was washed with sodium hydrogen carbonate solution, water and saturated brine, and dried with anhydrous magnesium sulfate, and the solvent was evaporated to give methyl 7-[4-(3-ethoxypropoxy) phenyl]-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.36g) as colorless crystals.

mp 112 - 113°C.
1H-NMR (8 ppm, CDC13) 1.22 (3H, t, J = 7.0 Hz) , 2.03 - 2. 15 (2H, m), 2.95 (2H, t, J = 4.8 Hz), 3.52 (2H, q, J = 7.0 Hz), 3.63 (2H, t, J = 6.3 Hz), 3.84 (3H, s), 3.84 (2H, t, J -4.8 Hz), 4.13 (2H, t, J = 6.3 Hz), 7.01 (2H, d, J = 8.8 Hz), 7.17 (1H, d, J = 8.2 Hz), 7.52 (2H, d, J = 8.8 Hz), 7.56 (1H, dd, J = 2.2, 8.8 Hz) , 7.68 (1H, d, J = 2.2 Hz) , 7.75 (1H, s), 8.53 (1H, s).
IR (KBr) v: 2951, 2872, 1709, 1678 cml.
Anal. Calcd. for CZ9HZ.,N05~0.2H20: C, 69.78; H, 6.69; N, 3.39.
Found C, 69.98: H, 6.79; N, 3.28.
Reference Example 40 In methanol (25m1) and THF (25m1) was dissolved methyl 7-[4-(3-ethoxypropoxy)phenyl]-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.31g). To the solution was added 1N sodium hydroxide solution (8m1), and the mixture was stirred at 50°C for 1.5 hours and concentrated. To the residue was added water, and the mixture was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated to give 7-[4-(3-ethoxypropoxy)phenyl]-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.3g) as colorless crystals.

mp 179 - 181°C.
1H-NMR (8 ppm, CDC13) 1.22 (3H, t, J = 7. 1 Hz) , 2.03 - 2. 15 (2H, m), 2.97 (2H, t, J = 5.5 Hz), 3.52 (2H, q, J = 7.1 Hz), 3. 63 (2H, t, J = 6.3 Hz) , 3. 88 (2H, t, J = 5. 5 Hz) , 4. 13 (2H, t, J = 6.0 Hz), 7.01 (2H, d, J = 8.8 Hz), 7.19 (1H, d, J = 8. 1 Hz) , 7 . 52 (2H, d, J = 8. 8 Hz) , 7. 58 (1H, dd, J =
2.0, 8. 1 Hz) , 7. 69 (1H, d, J = 2. 0 Hz) , 7. 85 (1H, s) , 8.55 (1H, s) .
IR (KBr) v: 3036, 2870, 1682 cml.
Anal. Calcd. for C23HZSN05: C, 69.86; H, 6.37; N, 3.54. Found C, 69.64; H, 6.32; N, 3.55.
Reference Example 41 A mixture of methyl 7-bromo-1-(t-butoxycarbonyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (1.0g), 3,4-diethoxyphenyl borate (0.63g), 1M potassium carbonate solution (8m1), ethanol (8m1) and toluene (50m1) was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakis(triphenylphosphine)palladium (0.12g), and the mixture was refluxed overnight under argon atmosphere and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give methyl 1-benzazepine-4-carboxylate (1.3g) as colorless crystals.
mp 168 - 173°C.
1H-NMR (8 ppm, CDC13) 1.45 - 1.53 (15H, m), 2.90 (2H, t, J =
5.0 Hz) , 3. 68 (2H, br) , 3. 83 (3H, s) , 4.09 - 4.23 (4H, m) , 6 . 95 ( 1H, d, J = 9 . 2 Hz ) , 7 . 09 - 7 . 14 ( 2H, m) , 7 . 40 - 7 . 52 ( 2H, m) , 7 . 57 ( 1H, s ) , 7 . 7 4 ( 1H, s ) .
IR (KBr) v: 2980, 1705 cm 1.
Anal. Calcd. for Cz~H33NO6: C, 69.36; H, 7.11; N, 3.00. Found C, 69.17; H, 7.11; N, 2.93.
Reference Example 42 In ethyl acetate (50m1) was dissolved methyl 1-(t-butoxycarbonyl)-7-(3,4-diethoxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (1.3g). To the solution was added 6N hydrochloric acid (lOml), and the mixture was stirred at 80°C for 1 hour, neutralized with 1N sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated to give methyl 7-(3,4-diethoxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.7g) as yellow crystals.
mp 159 - 164°C.
1H-NMR (8 ppm, CDC13) 1.43 - 1.52 (6H, m) , 2.89 (2H, t, J =
4.8 Hz), 3.41 (2H, t, J - 4.8 Hz), 3.81 (3H, s), 4.08 -4.22 (4H, m), 6.67 (1H, d, J = 8.4 Hz), 6.92 (1H, d, J -9.2 Hz), 7.03 - 7.07 (2H, m), 7.31 (1H, dd, J - 2.2, 8.2 Hz), 7.45 (1H, d, J = 2.2 Hz), 7.73 (1H, s).
IR (KBr) v: 3391, 2980, 1688 cml.
Anal. Calcd. for CZZH2sN04~0.2H20: C, 71.21; H, 6.90 N, 3.77.
Found C, 71.23; H, 6.88; N, 3.67.
Reference Example 43 To anhydrous acetic acid (0.22m1) was added dropwise formic acid (O.llml) under ice-cooling, and the mixture was stirred under nitrogen atmosphere at 50°C for 2 hours.
To the mixture was added THF (2m1) and then was added dropwise, under ice-cooling, a solution of methyl 7-(3,4-diethoxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxy late (0.35g) in THF (20m1), and the mixture was stirred at room temperature overnight. The solvent was evaporated, and to the residue was added water. The mixture was extracted with ethyl acetate. The organic layer was washed with sodium hydrogen carbonate solution, water and saturated brine, and dried with anhydrous magnesium sulfate, and the solvent was evaporated to give methyl 7-(3,4-diethoxyphenyl)-1-formyl-2,3-dihydro-1H-1-benzazepine-carboxylate (0.35g) as colorless crystals.
mp 152 - 153°C .
1H-NMR (b ppm, CDC13) 1.45 - 1. 54 (6H, m) , 2. 95 (2H, t, J =
5.3 Hz), 3.82 - 3.88 (5H, m), 4.10 - 4.24 (4H, m), 6.97 (1H, d, J = 8.8 Hz), 7.11 - 7.19 (3H, m), 7.56 (1H, dd, J = 2.2, 8.4 Hz) , 7. 67 (1H, d, J = 2.2 Hz) , 7.76 (1H, s) , 8.53 (1H, s) .
IR (KBr) v: 2980, 1709, 1678 cml.
Anal. Calcd. for C23Hz5N05~0.2H20: C, 69.23 H, 6.42; N, 3.51.
Found C, 69.39; H, 6.39; N, 3.48.
Reference Example 44 In methanol (25m1) and THF (25m1) was dissolved methyl 7-(3,4-diethoxyphenyl)-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.33g). To the solution was added 1N sodium hydroxide solution (8m1), and the mixture was stirred at room temperature overnight and concentrated. To the residue was added water, and the mixture was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated to give 7-(3,4-diethoxyphenyl)-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.32g) as colorless crystals.
mp 228 - 233°C (dec.).
1H-NMR (b ppm, CDC13) 1.49 (3H, t, J = 7.0 Hz) , 1.50 (3H, t, J = 7.0 Hz), 2.97 (2H, t, J = 5.5 Hz), 3.88 (2H, t, J = 5.5 Hz) , 4. 11 - 4.24 (4H, m) , 6. 97 (1H, d, J = 8.7 Hz) , 7. 11 -7.21 (3H, m) , 7. 59 (1H, dd, J = 2. 0, 8.7 Hz) , 7. 69 (1H, d, J = 2.0 Hz), 7.86 (1H, s), 8.55 (1H, s).
IR (KBr) v: 2980, 1682, 1669 cml.
Anal. Calcd. for Cz2H23N05: C, 69.28; H, 6.08; N, 3.67. Found C, 69.31; H, 6.23; N, 3.60.
Reference Example 45 A mixture of methyl 7-bromo-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.25g), 4-(2-butoxyethoxy)phenyl borate (0.23g), 1M potassium carbonate solution (2.5m1), ethanol (2.5m1) and toluene (25m1) was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakis(triphenylphosphine)palladium (0.04g), and the mixture was refluxed overnight under argon atmosphere and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give methyl 7-[4-(2-butoxyethoxy)phenyl]-1-formyl-2.3-dihydro-1H-1-benzazepine-4-carboxylate (0.23g) as colorless oil.
1H-NMR (8 ppm, CDC13) 0. 94 (3H, t, J = 7.2 Hz) , 1. 34 - 1.45 (2H, m), 1.55 - 1.69 (2H, m), 2.94 (2H, t, J - 5.0 Hz), 3.56 (2H, t, J = 6.6 Hz), 3.79 - 3.87 (7H, m), 4.18 (2H, t, J = 5.0 Hz), 7.02 (2H, d, J = 9.2 Hz), 7.17 (1H, d, J = 8.4 Hz), 7.48 - 7.58 (3H, m), 7.68 (1H, d, J - 2.2 Hz), 7.75 (1H, s), 8.53 (1H, s) .
IR (neat) v: 2938, 2870, 1713, 1682 cml.
Reference Example 46 In methanol (25m1) and THF (25m1) was dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-1-formyl-2,3-dihydro-1H-1-benzaz epine-4-carboxylate (0.23g). To the solution was added 1N sodium hydroxide solution (5m1), and the mixture was stirred at 55°C for 1.5 hours and concentrated. To the residue was added water, and the mixture was neutralized withlIN hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated to give 7-[4-(2-butoxyethoxy)phenyl)-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.24g) as colorless amorphous.
1H-NMR (8 ppm, CDC13) 0. 94 (3H, t, J = 7.3 Hz) , 1.27 - 1. 45 (2H, m), 1.55 - 1.66 (2H, m), 2.97 (2H, t, J - 4.9 Hz), 3.57 (2H, t, J = 6.8 Hz) , 3. 80 - 3. 90 (4H, m) , 4. 18 (2H, t, J = 4.9 Hz), 7.06 (2H, d, J = 8.8 Hz), 7.19 (1H, d, J = 8.2 Hz), 7.52 (2H, d, J = 8.8 Hz), 7.58 (1H, dd, J = 2.0, 8.2 Hz), 7.69 (1H, d, J = 2.0 Hz), 7.85 (1H, s), 8.55 (1H, s).
IR (KBr) v: 2955, 2934, 2867, 1682, 1669 cml.
Reference Example 47 A mixture of methyl 7-bromo-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.2g), 4-[N-(2-ethoxyethyl)-N-methylamino]phenyl borate (0.17g), potassium carbonate (0.2g), water (1.1m1), ethanol (l.lml) and toluene (10.7m1) was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakis(triphenylphosphine)palladium (0.03g), and the mixture was refluxed overnight under argon atmosphere and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give methyl 7-[4-[N-(2-ethoxyethyl)-N-methylamino]phenyl]-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.22g) as colorless amorphous.
1H-NMR (8 ppm, CDC13) 1.21 (3H, t, J = 7.0 Hz) , 2. 91 - 2. 97 (2H, m), 3.05 (3H, s), 3.52 (2H, q, J - 7.0 Hz), 3.58 -3. 63 (4H, m) , 3.81 - 3. 88 (2H, m) , 3.84 (3H, s) , 6. 81 (2H, d, J = 8.8 Hz), 7.14 (1H, d, J = 8.2 Hz), 7.46 - 7.57 (3H, m), 7.67 (1H, d, J = 2.0 Hz), 7.75 (1H, s), 8.52 (1H, s).
IR (KBr) v: 1707, 1678, 1610, 1503, 1358, 1261, 1234, 1196 cm 1.
Reference Example 48 In methanol (6.6m1) and THF (4.4m1) was dissolved methyl 7-[4-[N-(2-ethoxyethyl)-N-methylamino]phenyl)-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.22g).
To the solution was added 1N sodium hydroxide solution (2.2m1), and the mixture was stirred at room temperature overnight and concentrated. To the residue was added water, and the mixture was neutralized with 1N
hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated to give 7-[4-[N-(2-ethoxyethyl)-N-methylamino]phenyl]-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.18g) as colorless amorphous.
1H-NMR (8 ppm, CDC13) 1. 10 ( 3H, t, J = 7 . 4 Hz ) , 2 . 68 - 2 . 81 (2H, m), 2.97 (3H, s), 3.26 - 3.38 (2H, m), 3.44 (2H, q, J
- 7.0 Hz) , 3.54 (3H, s) , 3. 68 - 3.73 (2H, m) , 6. 79 (2H, d, J = 8.8 Hz), 7.36 (1H, d, J = 8.8 Hz), 7.56 - 7.73 (4H, m), 7.86 (1H, s), 8.52 (1H, s).
IR (KBr) v: 2975, 2876, 1678, 1611, 1503, 1312, 1431, 1292, 1273, 1194, 1117, 810 cm 1.
Reference Example 49 A mixture of methyl 7-bromo-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.2g), 4-[N-(2-ethoxyethyl)-N-ethylamino]phenyl borate (0.46g), 1M potassium carbonate solution (3.2m1), ethanol (3.2m1) and toluene (25m1) was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakis(triphenylphosphine)palladium (0.03g), and the mixture was refluxed overnight under argon atmosphere and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give methyl 7-[4-[N-(2-ethoxyethyl)-N-ethylamino]phenyl]-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.23g) as green amorphous.
1H-NMR (8 ppm, CDC13) 1.17 - 1.26 (6H, m), 2.94 (2H, t, J =
4.8 Hz), 3.42 - 3.64 (8H, m), 3.82 - 3.87 (5H, m), 6.78 (2H, d, J = 8. 8 Hz) , 7. 13 (1H, d, J = 8. 1 Hz) , 7. 47 (2H, d, J =
8.8 Hz), 7.54 (1H, dd, J = 2.1, 8.1 Hz), 7.66 (1H, d, J =
2.1 Hz), 7.75 (1H, s), 8.51 (1H, s).
IR (KBr) v: 2973, 2868, 1709, 1678 crril.
Reference Example 50 In methanol (25m1) and THF (25m1) was dissolved methyl 7-[4-[N-(2-ethoxyethyl)-N-ethylamino]phenyl]-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.23g).
To the solution was added 1N sodium hydroxide solution (5.5m1), and the mixture was stirred at room temperature overnight and concentrated. To the residue was added water, and the mixture was neutralized with 1N
hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated to give 7-[4-[N-(2-ethoxyethyl)-N-ethylamino]phenyl]-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.2g) as pale green crystals.
mp 182 - 184°C.
1H-NMR (8 ppm, CDC13) 1. 17 - 1. 30 ( 6H, m) , 2 . 97 ( 2H, t, J =
5.7 Hz), 3.43 - 3.65 (8H, m), 3.87 (2H, t, J - 5.7 Hz), 6.79 (2H, d, J - 8.8 Hz), 7.16 (1H, d, J = 8.4 Hz), 7.48 (2H, d, J = 8. 8 Hz) , 7.58 (1H, dd, J = 2.0, 8.4 Hz) , 7. 68 (1H, d, J = 2.0 Hz), 7.86 (1H, s), 8.54 (1H, s).
IR (KBr) v: 2973, 2872, 1682 cm 1.
Reference Example 51 A mixture of methyl 7-bromo-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.25g), 4-[N-ethyl-N-(2-propoxyethyl)amino]phenyl borate (0.3g), 1M potassium carbonate solution (2.5m1), ethanol (2.5m1) and toluene (25m1) was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakis(triphenylphosphine)palladium (0.04g), and the mixture was refluxed overnight under argon atmosphere and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give methyl 7-[4-[N-ethyl-N-(2-propoxyethyl)amino]phenyl]-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.31g) as green oil.
1H-NMR (8 ppm, CDC13) 0 . 93 ( 3H, t, J = 7 . 3 Hz ) , 1 . 21 ( 3H, t, J = 7.0 Hz), 1.59 - 1.66 (2H, m), 2.94 (2H, t, J = 5.2 Hz), 3. 39 - 3. 64 (8H, m) , 3. 82 - 3. 87 (5H, m) , 6. 78 (2H, d, J =
9.0 Hz), 7.14 (1H, d, J = 8.2 Hz), 7.47 (2H, d, J = 9.0 Hz), 7.55 (1H, dd, J = 2.0, 8.2 Hz), 7.66 (1H, d, J = 2.0 Hz), 7.75 (1H, s), 8.52 (1H, s).
IR (neat) v: 2942, 2867, 1709, 1682 cml.
Reference Example 52 In methanol (25m1) and THF (25m1) was dissolved methyl 7-[4-[N-ethyl-N-(2-propoxyethyl)amino]phenyl]-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.31g).
To the solution was added 1N sodium hydroxide solution (7m1), and the mixture was stirred at 60°C for 1.5 hours and concentrated. To the residue was added water, and the mixture was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated to give 7-[4-[N-ethyl-N-(2-propoxyethyl)amino]phenyl]-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.29g) as pale yellow crystals.
mp 169 - 171°C.
1H-NMR (8 ppm, CDC13) 0 . 93 ( 3H, t, J = 7 . 5 Hz ) , 1. 21 ( 3H, t, J = 7.0 Hz), 1.56 - 1.66 (2H, m), 2.96 (2H, t, J = 5.0 Hz), 3. 39 - 3. 62 (8H, m) , 3. 87 (2H, t, J = 5. 0 Hz) , 6. 78 (2H, d, J = 8.8 Hz), 7.16 (1H, d, J = 8.0 Hz), 7.47 (2H, d, J = 8.8 Hz), 7.58 (1H, dd, J = 2.0, 8.0 Hz), 7.68 (1H, d, J = 2.0 Hz), 7.84 (1H, s), 8.54 (1H, s) .
IR (KBr) v: 2967, 2870, 1680 cml.
Reference Example 53 In THF (50m1) were dissolved methyl 7-(4-morpholinophenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.7g) and pyridine (1.2m1). To the solution was added methanesulfonic anhydride (1.5g), and the mixture was stirred under nitrogen atmosphere at 50 for 3 hours. The solvent was evaporated, and to the residue was added water. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give methyl 7-methanesulfonyl-7-(4-morpholinophenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.4g) as pale yellow crystals.
mp 224 - 226°C (dec.).
1H-NMR (8 ppm, CDC13) 2.78 (3H, s), 3.05 (2H, t, J = 5.0 Hz), 3.21 - 3.26 (4H, m) , 3.85 - 3. 92 (9H, m) , 6. 99 (2H, d, J =
9.2 Hz), 7.50 - 7.58 (3H, m), 7.63 - 7.69 (2H, m), 7.80 (1H, s) .
IR (KBr) v: 2953, 1709 cml.
Reference Example 54 In methanol (100m1) and THF (100m1) was dissolved methyl 1-methanesulfonyl-7-(4-morpholinophenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.4g). To the solution was added 1N sodium hydroxide solution (lOml), and the mixture was stirred at room temperature overnight.
To the mixture was added 1N sodium hydroxide solution (5m1), and the mixture was stirred at 60°C for 1.5 hours and concentrated. To the residue was added water, and the mixture was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated to give 1-methanesulfonyl-7-(4-morpholinophenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.36g) as pale yellow crystals.
mp 264 - 275°C (dec.).
1H-NMR (8 ppm, CDC13 + CD30D) 2 . 7 9 ( 3H, s ) , 3 . 02 ( 2H, t, J =

5.1 Hz), 3.21 - 3.26 (4H, m), 3.84 - 3.92 (6H, m), 7.00 (2H, d, J = 8 . 8 Hz ) , 7 . 50 - 7 . 58 ( 3H, m) , 7 . 64 - 7 . 68 ( 2H, m) , 7.83 (1H, s).
IR (KBr) v: 2969, 2832, 1671 cml.
Anal . Calcd. for CZZHZQNZOSS : C, 61. 66; H, 5 . 65 ~ N, 6. 54 .
Found C, 61.48: H, 5.81; N, 6.25.
Reference Example 55 In THF (25m1) were dissolved methyl 7-(4-ethoxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.25g) and pyridine (0.6m1). To the solution was added methanesulfonic anhydride (0.67g), and the mixture was stirred under nitrogen atmosphere at 40°C overnight. To the mixture was added methanesulfonic anhydride (0.13g), and the mixture was stirred at 40°C for 4 hours. The solvent was evaporated. To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give methyl 7-(4-ethoxyphenyl)-1-methanesulfonyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.14g) as pale yellow crystals.
mp 175 - 181°C.
1H-NMR (8 ppm, CDC13) 1.45 (3H, t, J = 7. 1 Hz) , 2.78 (3H, s) , 3.05 (2H, J = 4.9 Hz), 3.84 - 3.89 (5H, m), 4.09 (2H, t, q, J = 7.1 Hz),6.98 (2H, d, J = 8.8 Hz),7.49 - 7.57 (3H, m), 7.63 (1H, J = 2.2 Hz), 7.67 (1H, d, J = 8.4 Hz), 7.80 d, (1H, s) .
IR (KBr) v: 2984, 1711 cml Reference Example 56 In methanol (25m1) and THF (25m1) was dissolved methyl 7-(4-ethoxyphenyl)-1-methanesulfonyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.14g). To the solution was added 1N sodium hydroxide solution (3m1), and the mixture was stirred at room temperature overnight and concentrated. To the residue was added water, and the mixture was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated to give 7-(4-ethoxyphenyl)-1-methanesulfonyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.13g) as pale yellow crystals.
mp 237 - 242°C (dec. ) .
1H-NMR (8 ppm, CDC13) 1.46 (3H, t, J = 7.0 Hz) , 2. 81 (3H, s) , 3.08 (2H, t, J = 5.9 Hz), 3.89 (2H, t, J = 5.9 Hz), 4.10 (2H, q, J = 7.0 Hz), 6.99 (2H, d, J = 8.8 Hz), 7.52 (2H, d, J = 8.8 Hz), 7.58 (1H, dd, J = 2.0, 8.4 Hz), 7.65 (1H, d, J
- 2.0 Hz), 7.70 (1H, d, J = 8.4 Hz), 7.91 (1H, s).

IR (KBr) v: 2984, 1669 cm 1.
Reference Example 57 In THF (30m1) were dissolved methyl 7-[4-(2-ethoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.25g) and pyridine (0.5m1). To the solution was added methanesulfonic anhydride (0.6g), and the mixture was stirred under nitrogen atmosphere at 50°C
overnight. To the mixture was added methanesulfonic anhydride (0.1g), and the mixture was stirred at 50°C for 2 hours. The solvent was evaporated. To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give methyl 7-[4-(2-ethoxyethoxy)phenyl.]-1-methanesulfonyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.13g) as pale yellow crystals.
mp 143 - 146C.

1H-NMR (b ppm, CDC13) 1.27 (3H, t, = Hz) , 2. 78 (3H, J 6. s) , 3.06 (2H, t, = 5.2 Hz) , 3. (2H, q, = 6. 9 Hz) , 3.81 3. 89 (7H, m) 4. 19 (2H, t, = Hz) 7.03 (2H, d, J
, J 4. , =

8.8 Hz), 7.49 - 7.57 (3H, m), 7.64 (1H, d, J - 2.0 Hz), 7.68 (1H, d, = 8.4 Hz), 7.81 (1H, s).
J

IR (KBr) v: l.
2932, 2872, cm Reference Example 58 In methanol (20m1) and THF (20m1) was dissolved methyl 7-[4-(2- ethoxyethoxy)phenyl]-1-methanesulfonyl-2,3-dihydro-1-benzazepine-4-carboxylate (0.13g). To the solution was added 1N sodium hydroxide solution (3m1), and the mixture was stirred at room temperature overnight and concentrated. To the residue was added water, and the mixture was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated to give 7-[4-(2-ethoxyethoxy)phenyl]-1-methanesulfonyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.12g) as pale yellow crystals.
mp 222 - 225°C.
1H-NMR (8 ppm, CDC13) 1.27 (3H, t, J = 7. 1 Hz) , 2. 81 (3H, s) , 3.08 (2H, t, J = 5. 1 Hz) , 3. 63 (2H, q, J = 7. 1 Hz) , 3. 81 -3.91 (4H, m), 4.19 (2H, t, J = 4.8 Hz), 7.03 (2H, d, J -8.8 Hz) , 7.52 (2H, d, J = 8.8 Hz) , 7.57 (1H, dd, J = 2.2, 9.0 Hz), 7.64 (1H, d, J = 2.2 Hz), 7.67 (1H, d, J = 9.0 Hz), 7 . 90 ( 1H, s ) .
IR (KBr) v: 2978, 2872, 1694, 1669 cml.
Reference Example 59 In THF (35m1) were dissolved methyl 7-[4-(3-ethoxypropoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.4g) and pyridine (0.75m1). To the solution was added methanesulfonic anhydride (0.92g), and the mixture was stirred under nitrogen atmosphere at room temperature overnight. To the mixture was added methanesulfonic anhydride (0.25g), and the mixture was stirred at 50°C overnight. The solvent was evaporated.
To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give methyl 7-[4-(3-ethoxypropoxy)phenyl]-1-methanesulfonyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.26g) as pale yellow crystals.
mp 127 - 129°C.
1H-NMR (8 ppm, CDC13) 1 . 22 ( 3H, t, J = 7 . 0 Hz ) , 2 . 02 - 2 . 15 (2H, m) , 2. 78 (3H, s) , 3. 05 (2H, t, J = 5. 5 Hz) , 3. 51 (2H, q, J - 7.0 Hz), 3.62 (2H, t, J - 6.2 Hz), 3.85 (3H, s), 3.86 (2H, t, J = 5.5 Hz), 4.12 (2H, t, J = 6.2 Hz), 7.00 (2H, d, J = 8.8 Hz), 7.51 (2H, d, J = 8.8 Hz), 7.55 (1H, dd, J = 2 . 2, 8 . 4 Hz ) , 7 . 63 ( 1H, d, J = 2 . 2 Hz ) , 7 . 67 ( 1H, d, J
- 8.4 Hz), 7.80 (1H, s).
IR (KBr) v: 2951, 2872, 1711 cml.
Reference Example 60 In methanol (25m1) and THF (25m1) was dissolved methyl 7-[4-(3-ethoxypropoxy)phenyl]-1-methanesulfonyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.22g). To the solution was added 1N sodium hydroxide solution (5m1), and the mixture was stirred at room temperature overnight and concentrated. To the residue was added water, and the mixture was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated to give 7-[4-(3-ethoxypropoxy)phenyl]-1-methanesulfonyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.23g) as pale yellow crystals.
mp 210 - 212C.

1H-NMR (8 ppm, CDC13) 1. ( 3H, t, = 7 . 2 Hz ) , 2 2 22 J . 03 - .

(2H, m) , 2. 81 (3H, , J = 5.5 Hz) , 3.52 (2H, s) 3.

(2H, t, q, J = 7. 2 Hz) , 3. (2H, t, J = Hz) , 3.89 (2H, J
63 6. 0 t, =

5.5 Hz), 4.13 (2H, J 6.2 Hz), Hz), t, = 7.00 (2H, d, J =
8.8 7.52 (2H, d, J = 8.8 Hz), 7.57 (1H, dd, J = 1.8, 8.4 Hz), 7.65 (1H, d, J = 1.8 Hz), 7.69 (1H, d, J - 8.4 Hz), 7.91 ( 1H, s ) .
IR (KBr) v: 3036, 2870, 1671 cml.
Anal. Calcd. for C23H2~NO6S: C, 62.00: H, 6.11; N, 3.14.
Found C, 62.17; H, 5.99; N, 3.17.
Reference Example 61 In dimethyl carbonate (15m1) was dissolved 7-bromo-1,2,3,4-tetrahydro-1-benzazepin-5-one (0.68g). To the solution was added sodium methoxide (0.92g), and the mixture was refluxed under nitrogen atmosphere for 8 hours and poured into ice-water. To the mixture was added 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give pale yellow oil (0.88g), which was dissolved in THF (30m1). To the solution was added sodium borohydride (0.1g) at -40°C and then was added dropwise methanol (3m1), and the mixture was stirred at -15°C for 1 hour. To the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated. The residue was dissolved in THF (25m1), and to the solution was added triethylamine (0.7m1), and then was added dropwise, under ice-cooling, methanesulfonyl chloride (0.6m1). Under nitrogen atmosphere, the mixture was stirred at room temperature overnight, and to the mixture was added dropwise DBU (2.5m1) at room temperature. The mixture was refluxed for 30 minutes, and the solvent was evaporated. To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give methyl 7-bromo-1-methoxycarbonyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.3g) as colorless crystals.
mp 135 - 136°C.
1H-NMR (8 ppm, CDC13) 2. 92 (2H, t, J - 5. 1 Hz) , 3. 70 (2H, br), 3.74 (3H, s), 3.82 (3H, s), 7.26 (1H, br), 7.42 (1H, dd, J = 2.2, 8.4 Hz), 7.56 - 7.57 (2H, m).
IR (KBr) v: 2951, 1713 cml.
Anal. Calcd. for C14H14BrN09: C, 49.43; H, 4.15; N, 4.12.
Found C, 49.53; H, 4.08; N, 4.06.
Reference Example 62 A mixture of methyl 7-bromo-1-methoxycarbonyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.3g), 4-morpholinophenyl borate (0.22g), 1M potassium carbonate solution (2.5m1), ethanol (2.5m1) and toluene (25m1) was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakis(triphenylphosphine)palladium (0.04g), and the mixture was refluxed overnight under argon atmosphere and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give methyl 1-methoxycarbonyl-7-(4-morpholinophenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.31g) as pale yellow crystals.
mp 216 - 220°C.
1H-NMR (8 ppm, CDC13) 2. 94 (2H, t, J = 5.4 Hz) , 3.20 - 3.25 (4H, m), 3.75 (2H, br), 3.76 (3H, br), 3.83 (3H, s), 3.87 -3.92 (4H, m), 6.99 (2H, d, J = 9.0 Hz), 7.39 (1H, br), 7.50 - 7.55 (3H, m), 7.60 (1H, s), 7.73 ( 1H, s).
IR (KBr) v: 2953, 1713 cm 1.
Anal. Calcd. for C24H~6N205~0.2H20: C, 67.65; H, 6.25: N, 6.57.
Found C, 67.50; H, 6.10; N, 6.58.
Reference Example 63 In methanol (40m1) and THF (60m1) was dissolved methyl 1-methoxycarbonyl-7-(4-morpholinophenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.31g). To the solution was added 1N sodium hydroxide solution (5m1), and the mixture was stirred at room temperature overnight.
To the mixture was added 1N sodium hydroxide solution (2.5m1), and the mixture was stirred at room temperature overnight and concentrated. The residue was neutralized with 1N hydrochloric acid, precipitated crystals were filtered and washed with water to give 1-methoxycarbonyl-7-(4-morpholinophenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.29g) as colorless crystals.
mp 274 - 279°C (dec.).
1H-NMR (b ppm, DMSO-d6 ) 2 . 7 8 ( 2H, t-li ke ) , 3 . 16 - 3 . 18 ( 4H, m) , 3. 60 (2H, br) , 3. 66 (3H, s) , 3.75 - 3.77 (4H, m) , 7.03 (2H, d, J = 8. 6 Hz) , 7.40 (1H, d, J = 8.4 Hz) , 7.58 - 7. 69 (4H, m), 7.79 (1H, s), 12.65 (1H, br).
IR (KBr) v: 2969, 1705, 1678 cm 1.
Anal. Calcd. for C23H24N205'0.5H20: C, 66.17; H, 6.04; N, 6.71.
Found C, 66.15; H, 5.74; N, 6.68.
Reference Example 64 In pyridine (lO.Oml) were dissolved ethyl 4-(4-bromo-2-formylphenyl)aminobutyrate (3.16g) and tosyl chloride (2.88g), and the mixture was stirred at 50°C for 62 hours. The mixture was diluted with ethyl acetate, washed with 1N hydrochloric acid and saturated brine, and the organic layer was dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified with silica gel column chromatography (150g, hexane . ethyl acetate = 6 .
1 ~ 4:1) to give ethyl 4-(4-bromo-2-formylphenyl)-4-[(4-methylphenyl)sulfonyl]aminobutyrate (1.478, 310) as brown oil.

1H-NMR (200 MHz, CDC13) 8 1.23 (3H, t, J = 7.0 Hz), 1.77 (2H, quint, J = 7.2 Hz), 2.35 (2H, t, J = 7.1 Hz), 2.45 (3H, s), 3.27 - 3.38 (1H, m) , 3.88 - 3. 96 (1H, m) , 4.09 (2H, q, J =
6.9 Hz), 6.60 (1H, d, J = 8.6 Hz), 7.29 (2H, d, J = 9.2 Hz), 7.44 (2H, d, J = 8.4 Hz), 7.59 (1H, dd, J = 8.5, 2.5 Hz), 8.15 (1H, d, J = 2.6 Hz), 10.35 (1H, s).
IR (KBr) 1732, 1694, 1474, 1377, 1350, 1184, 1163, 723, 655, 579 cm 1.
Reference Example 65 In a mixture of t-butanol and toluene (1:10, v/v, 66.0m1) was dissolved ethyl 4-(4-bromo-2-formylphenyl)-4-[(4-methylphenyl)sulfonyl]aminobutyrate (1456mg). To the solution was added at room temperature potassium t-butoxide (384mg), and the mixture was stirred at 100°C
for I hour. To the mixture was added 1N hydrochloric acid to convert weakly acidic solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified with silica gel column chromatography (75g, hexane . ethyl acetate = 6 . 1) to give ethyl 7-bromo-1-[(4-methylphenyl)sulfonyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (413mg, 30~) as yellow amorphous.
1H-NMR (200 MHz, CDC13) b 1.29 (3H, t, J = 7.2 Hz), 2.35 (3H, s), 2.86 (2H, td, J = 5.8, 1.4 Hz), 3.87 (2H, t, J = 6.1 Hz), 4.19 (2H, q, J = 7.1 Hz), 7.13 (2H, d, J = 8.0 Hz), 7.15 - 7.19 (1H, m), 7.39 - 7.55 (5H, m).
IR (KBr) 1709, 1485, 1350, 1246, 1194, 1163, 1090, 710, 696, 662 cm 1.
Reference Example 66 In a mixture of water . ethanol . toluene (1 . 1 .
v/v, 18.0m1) were dissolved 4-(4-morpholino)phenyl borate (278mg) and ethyl 7-bromo-1-[(4-10 methylphenyl)sulfonyl]-2,3- dihydro-1H-1-benzazepine-4-carboxylate (403mg). To the solution was added potassium carbonate (297mg), and the mixture was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (4lmg), and the mixture was refluxed under argon atmosphere for 13 hours. The mixture was diluted with ethyl acetate, and washed with water and saturated brine.
The organic layer was dried with anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified with silica gel column chromatography (45g, hexane . ethyl acetate = 4 .
1 -~ 3 . 1) to give ethyl 7-[(4-methylphenyl)sulfonyl]-7-[4-(4-morpholino)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (460mg, 960) as yellow crystals.
1H-NMR (200 MHz, CDC13) 8 1.30 (3H, t, J = 7.2 Hz), 2.34 (3H, s), 2.87 (2H, t, J - 5.3 Hz), 3.23 (4H, t, J - 4.9 Hz), 3.90 (4H, t, J = 4.8 Hz), 3.90 - 3.95 (2H, m), 4.20 (2H, q, J = 7.1 Hz), 6.99 (2H, d, J = 9.0 Hz), 7.12 (2H, d, J = 8.2 Hz), 7.36 (1H, s), 7.45 (2H, d, J = 8.4 Hz), 7.53 (2H, d, J
- 8.6 Hz), 7.46 - 7.68 (3H, m).
IR (KBr) 1705, 1609, 1493, 1348, 1233, 1161, 1123, 1092, 932, 818, 671 cm 1.
Reference Example 67 In THF (10.0m1) was dissolved methyl 7-[4-(4-morpholino)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (369mg), and to the solution were added pyridine (0.11m1) and acetyl chloride (0.086m1) at room temperature or at 0°C. The mixture was stirred at room , temperature for 30 minutes, and diluted with ethyl acetate and washed with water and saturated brine. The organic layer was dried with anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give methyl 1-acetyl-7-[4-(4-morpholino)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (400mg, 97°s) as pale yellow amorphous.
1H-NMR (200 MHz, CDC13) b 2.05 (3H, s), 2.74 - 3.19 (3H, m), 3.24 (4H, t, J = 4.8 Hz), 3.83 (3H, s), 3.90 (4H, t, J =
4.8 Hz), 4.73 - 4.85 (1H, m), 7.01 (2H, d, J - 8.8 Hz), 7.23 (1H, d, J = 8.2 Hz), 7.54 (2H, d, J = 8.8 Hz), 7.51 7.56 (1H, m), 7.67 (1H, d, J = 1.8 Hz), 7.74 (1H, s).

IR (KBr) 1709 ,1659, 1609, 1497, 1389, 1233, 1123 cml.
Reference Example 68 In a mixture of THF and ethanol (l:l,v/v, 10.0m1) was dissolved methyll-acetyl-7-[4-(4-morpholino)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (394m8). To the solution was added 1N sodium hydroxide solution (3.0m1), and the mixture was stirred at room temperature for 12 hours. To the mixture was added 1N hydrochloric acid to convert weakly acidic solution, and the mixture was extracted with ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 1-acetyl-7-[4-(4-morpholino)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (372m8, 98~) as pale yellow crystals.
1H-NMR (200 MHz, DMSO-d6) 8 1.95 (3H, s), 2.75 (3H, br), 3.17 (4H, t, J = 4.7 Hz), 3.76 (4H, t, J - 4.8 Hz), 4.54 (1H, br), 7.03 (2H, d, J = 8.8 Hz), 7.46 (1H, d, J = 8.2 Hz), 7.63 - 7.72 (4H, m), 7.88 (1H, s).
Reference Example 69 In THF (500m1) was dissolved methyl anthranylate (247.88, 130mo1). To the solution were added pyridine (205.78, 2.60m1) and tosyl chloride (260.28, 1.37mo1) at room temperature, and the mixture was stirred for 14.5 hours (overnight). To the mixture were added ethyl acetate and water to carry out extraction, and the organic layer was washed with 1N hydrochloric acid, water and saturated brine, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give crystals which were washed with ethyl acetate and IPE (isopropyl ether) to give white crystals of methyl N-tosylanthranylate (348.0g). The mother liquor was treated by the same procedure to give methyl N-tosylanthranylate (32.4g).
Yield, 380.4 g (96~).
mp 111 - 112°C.
1H-NMR (CDC13, 200 MHz) 8 2.36 (3H, s), 3.88 (3H, s), 7.03 (1H, td, J = 7.6, 1.7 Hz), 7.22 (2H, d, J = 8.0 Hz), 7.45 (1H, td, J = 7.9, 1.5 Hz), 7.67 - 7.78 (1H, m), 7.75 (2H, d, J - 8.4 Hz), 7.92 (1H, dd, J - 8.0, 1.6 Hz), 10.63 (1H, brs).
IR (KBr) 3173, 1688, 1493, 1260, 1161, 1090, 567 cm 1.
Reference Example 70 In 85~ acetic acid solution (1000m1) were suspended methyl N-tosylanthranylate (1008, 328mmo1) and sodium acetate (29.68, 361mmol). To the solution was added dropwise at room temperature a solution of bromine (21.0m1, 408mmo1) in 85~ acetic acid solution (100m1), and the mixture was stirred at 70°C for 2 hours. To the mixture was added sodium thiosulfate pentahydrate at room temperature, and excess bromine was reduced. The mixture was concentrated under reduced pressure, and to the residue were added water and ethyl acetate. The separated organic layer was washed with potassium carbonate solution and saturated brine and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give crystals, which were washed with IPE to give white crystals of methyl 5-bromo-N-tosylanthranylate (116.98). The mother liquor was treated by the same procedure to give methyl 5-bromo-N-tosylanthranylate (6:98).
Yield, 123.58 (988).
mp 123 - 124°C.
1H-NMR (CDC13, 200 MHz) 8 2.38 (3H, s), 3.89 (3H, s), 7.24 (2H,d,J=9.2Hz),7.53(lH,dd,J=8.8,2.2Hz),7.61 (1H, d, J = 8.6 Hz), 7.73 (2H, d, J = 8.0 Hz), 8.03 (1H, d, J = 2.2 Hz), 10.52 (1H, brs).
Reference Example 71 In a mixture of water . ethanol . toluene (1 . 1 .
10, v/v. 42.0m1) were dissolved 4-propoxyphenyl borate (746m8) and methyl 7-bromo-1-(t-butoxycarbonyl)-2,3 dihydro-1H-1-benzazepine-4-carboxylate (1320m8). To the solution was added potassium carbonate (1145m8), and the mixture was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (160m8), and the mixture was heated to reflux under argon atmosphere for 14.5 hours. The mixture was diluted with ethyl acetate, and washed with water and saturated brine, and the organic layer was dried with anhydrous magnesium sulfate.
The solvent was evaporated under reduced pressure, and the residue was purified with silica gel column chromatography (75g, hexane . ethyl acetate = 3 . 1) to give methyl 1-(t-butoxycarbonyl)-7-(4-ropoxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate as yellow amorphous. The obtained methyl 1-(t-butoxycarbonyl)-7-(4-propoxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate was dissolved in ethyl acetate (80m1). To the solution was added 6N hydrochloric acid (20m1) at room temperature, and the mixture was stirred at 100°C
for 30 minutes and neutralized with 1N sodium hydroxide and saturated sodium hydrogen carbonate solution. The separated organic layer was washed with saturated sodium hydrogen carbonate solution, water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give crystals, which were washed with ethyl acetate/hexane to give methyl 7-(4-propoxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (947mg) as yellow crystals. The mother liquor was concentrated, and the residue was purified with silica gel column chromatography (15g, hexane: ethyl acetate=4:1) to give desired product (147mg).
Yield, 1094mg (94~).
mp 134 - 137°C.
1H-NMR (200 MHz, CDC13) 8 1.05 (3H, t, J = 8.1 Hz), 1.83 (2H, sextet, J = 7.0 Hz), 2.88 (2H, t, J = 4.4 Hz), 3.40 (2H, t, J = 4.8 Hz) , 3. 81 (3H, s) , 3. 96 (2H, t, J = 6. 6 Hz) , 6. 67 (1H, d, J = 8.4 Hz), 6.90 - 6.98 (2H, m), 7.32 (1H, dd, J =
8.4, 2.2 Hz), 7.45 (2H, d, J = 8.4 Hz), 7.46 (1H, d, J -1.8 Hz), 7.73 (1H, s).
IR (KBr) 3384, 2963, 1698, 1609, 1499, 1269, 1242, 1209, 1177, 818 cm 1.
Anal. Calcd. for Cz1H23NOs (0.1H20 additive) : C, 74.36; H, 6.89 N, 4.13. Found C, 74.31; H, 6.81 N, 4.10.
Reference Example 72 To anhydrous acetic acid (0.65m1) was added formic acid (0.32m1) at 0°C, and the mixture was stirred at 60°C
for 2 hours, air-cooled and diluted with THF (lOml). In THF (lOml) was dissolved methyl 7-(4 propoxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (520mg), and the solution was added dropwise to the previously prepared solution of formic anhydride in THF, at 0°C. The mixture was stirred at room temperature for 1.5 hours. The solvent was evaporated under reduced pressure, and the residue was diluted with ethyl acetate, washed with saturated sodium hydrogen carbonate solution, water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give crystals, which were washed with ethyl acetate/hexane to give methyl 1-formyl-7-(4-propoxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (563mg) as white crystals.
mp 151.5 - 153°C.
1H-NMR (200 MHz, CDC13) 8 1.07 (3H, t, J = 7.5 Hz), 1.85 (2H, sextet, J = 7.1 Hz), 2.92 (2H, t, J = 5.1 Hz), 3.84 (3H, s), 3. 85 (2H, t, J = 5.5 Hz) , 3. 98 (2H, t, J = 6. 6 Hz) , 6. 98 7.02 (2H, m), 7.17 (1H, d, J = 8.0 Hz), 7.48 - 7.54 (2H, m), 7.56 (1H, dd, J = 8.2, 2.2 Hz) , 7.68 (1H, d, J = 2.0 Hz) , 7.76 (1H, s), 8.53 (1H, s).
IR (KBr) 1709, 1678, 1497, 1358, 1236, 1192, 824 crril.
Anal. Calcd. for CZZHzsN09: C, 72.31; H, 6.34; N, 3.83. Found C, 72.35; H, 6.45; N, 3.83.
Reference Example 73 In THF (15.0m1) was dissolved methyl 7-(4-propoxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (431mg). To the solution was added pyridine (1.0m1) and then was added a solution of methanesulfonic anhydride (l.llg) in THF (5.0 ml), at room temperature, and the mixture was stirred at 50°C for 15 hours. The mixture was diluted with ethyl acetate, and washed with water, 1N
hydrochloric acid, water and saturated brine, and the organic layer was dried with anhydrous magnesium sulfate.
The solvent was evaporated under reduced pressure to give crystals, which were washed with ethyl acetate to give methyl 1-methylsulfonyl-7-(4-propoxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (238mg) as white crystals.
The mother liquor was concentrated, and the residue was purified with silica gel column chromatography (15g, hexane . ethyl acetate = 2 . 1) to give desired product.
The obtained methyl 1-methylsulfonyl-7-(4-propoxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate was collected and dissolved in a mixture of THF and ethanol (1 . 1, v/v, 40m1). To the solution was added 1N sodium hydroxide solution (14.0m1), and the mixture was stirred at room temperature for 18 hours. The mixture was a little concentrated, and to the residue was added 1N
hydrochloric acid to convert weakly acidic solution. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give crystals, which were washed with ethyl acetate/hexane to give 1-methylsulfonyl-7-(4-propoxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (273mg, 53~) as white crystals.
mp 261 - 263°C (dec.).

1H-NMR (200 MHz, DMSO-d6) 8 1. (3H, t, J 7.3 Hz) 1.76 00 = , (2H, sextet, J = 7.0 Hz) , 2. (2H, t-like)3. (3H, s) 91 , 08 , 3.71 (2H, t-like ), 3.98 (2H, J = 6.6 Hz),7.02 (2H, d, t, J

- 8.6 Hz), 7.51 (1H, d, J = 8.4 Hz), 7.61 7.65 (1H, m), -7.67 (2H, d, J = 8.8 Hz), 7.75 (1H, s), J
7.86 (1H, -d, 1.4 Hz) .
IR (KBr) 1669, 1499, 1435, 1341, 1273, 1248, 1144, 970, 824, 787 cm 1.
Anal. Calcd. for CZIHz3NOsS (0.2H20 additive) : C, 62.27; H, 5.82: N, 3.46. Found C, 62.17 H, 5.87 N, 3.45.
Reference Example 74 In a mixture of THF and ethanol (1 . 1, v/v.
24.0m1 ) was dissolved methyl 1-formyl-7-(4-propoxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (501mg). To the solution was added 1N sodium hydroxide solution (15.0m1), and the mixture was stirred at room temperature for 16 hours. The mixture was a little concentrated, and to the residue was added 1N
hydrochloric acid to convert weakly acidic solution. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give crystals, which were washed with ethyl acetate/hexane to give 1-formyl-7-(4-propoxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (482mg) as white crystals.
mp 215 - 217°C.
1H-NMR (200 MHz, DMSO-d6) 8 1.03 (3H, t, J = 7.4 Hz), 1.71 1.84 (2H, m), 2.79 (2H, t, J = 5.4 Hz), 3.75 (2H, t, J =
5.6 Hz), 3.98 (2H, t, J = 6.5 Hz), 7.00 (2H, d, J = 8.8 Hz), 7.34 (1H, d, J = 8.4 Hz), 7.59 - 7.65 (3H, m), 7.73 (1H, s), 7.82 (1H, d, J = 1.6 Hz), 8.53 (1H, s).
IR (KBr) 1701, 1682, 1644, 1501, 1366, 1294, 1256, 1233, 1186, 820 cm 1.
Anal. Calcd. for C21HZ1N09: C, 71.78; H, 6.02; N, 3.99. Found C, 72.08; H, 6.12; N, 4.06.
Reference Example 75 In a mixture of water . ethanol . toluene (1 . 1 .
10, v/v, 42.0m1) were dissolved 4-ethoxy-3-fluorophenyl borate (754mg) and methyl 7-bromo-1-(t-butoxycarbonyl) 2,3-dhydro-1H-1-benzazepine-4-carboxylate (1305mg). To the solution was added potassium carbonate (1132mg), and the mixture was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (158mg), and the mixture was heated to reflux under argon atmosphere for 10 hours. The mixture was diluted with ethyl acetate, and washed with water and saturated brine, and the organic layer was dried with anhydrous magnesium sulfate.
The solvent was evaporated under reduced pressure, and the residue was purified with silica gel column chromatography (75g, hexane . ethyl acetate = 4 . 1) to give methyl 1-(t-butoxycarbonyl)-7-(4-ethoxy-3-fluorophenyl)-2,3-dihydoro-1H-1-benzazepine-4-carboxylate as yellow amorphous. The obtained methyl 1-(t-butoxycarbonyl)-7-(4-ethoxy-3-fluorophenyl)-2,3-dihydro-1-(t-butoxycarbonyl)-7-(4-ethoxy-3-fluorophenyl)-2,3-dihydoro-1H-1-benzazepine-4-carboxylate was dissolved in ethyl acetate (80m1). To the solution was added 1N
hydrochloric acid (15m1) at room temperature, and the mixture was stirred at 100°C for 1 hour and neutralized with 1N sodium hydroxide and saturated sodium hydrogen carbonate solution. To the mixture was added ethyl acetate, and the separated organic layer was washed with saturated sodium hydrogen carbonate solution, water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified with silica gel column chromatography (50g, hexane . ethyl acetate = 9 .
1 ~ 4 . 1 ~ 2 . 1) to give methyl 7-(4-ethoxy-3-fluorophenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (1007mg, 860) as yellow crystals.
mp 134 - 137°C.
1H-NMR (200 MHz, CDC13) 8 1.47 (3H, t, J = 7.0 Hz), 2.89 (2H, t, J - 4.4 Hz), 3.41 (2H, q, J - 4.8 Hz), 3.81 (3H, s), 4.14 (2H, q, J = 7.1 Hz), 4.63 (1H, brs), 6.67 (1H, d, J =
8.2 Hz), 6.94 - 7.03 (1H, m), 7.19 - 7.31 (3H, m), 7.44 (1H, d, J = 2.2 Hz), 7.71 (1H, s).
IR (KBr) 3385, 1696, 1624, 1503, 1478, 1435, 1312, 1292,1235, 1211, 1173 cml.
Anal. Calcd. for CZOHzoFN03: C, 70.37; H, 5.91 N, 4.10.
Found C, 70.35: H, 5.73 N, 4.03.
Reference Example 76 To anhydrous acetic acid (0.63m1) was added formic acid (0.31m1) at 0°C, and the mixture was stirred at 60°C
for 2 hours, cooled and diluted with THF (lOml). In THF
(lOml) was dissolved methyl 7-(4-ethoxy-3-fluorophenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (510mg), and the solution was added dropwise to the previously prepared solution of formic anhydride in THF, at 0°C.
The mixture was stirred at room temperature for 2 hours, and the solvent was evaporated under reduced pressure.
The residue was diluted with ethyl acetate, washed with saturated sodium hydrogen carbonate solution, water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give crystals, which were washed with ethyl acetate/hexane to give methyl 7-(4-ethoxy-3-fluoropheny)-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (490mg, 89°s) as white crystals.

mp 126 - 127.5C.

1H-NMR (200 MHz, CDC13) b 1.49 7.0 Hz), 2.95(2H, (3H, t, J =

td, J = 5.5, 1.1 Hz), 3.83 - 3.88 (2H, m), 3.84 (3H,s), 4.17 (2H, q, J = 7.1 Hz), 7.05 (1H, t, J = 8.7 z), 7.19 H

(1H, d, J = 8.0 Hz), 7.28 - 7.37 (2H, m), 7.54 (1H, dd, J
=

8 . 2, 2 . 2 Hz ) , 7 . 66 ( J = 2 . 2 Hz 7 . 75 s 8 1H, d, ) , ( 1H, ) .
, 54 (1H, s) .
IR (KBr) 1707, 1674, 1501, 1269, 1236 cml.
Anal. Calcd. for CZIHZoFN04: C, 68.28; H, 5.46; N, 3.79.
Found C, 68.18; H, 5.52; N, 3.70.
Reference Example 77 In THF (10.0m1) was dissolved methyl 7-(4-ethoxy-3-fluorophenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (345mg). To the solution was added pyridine (0.82m1), and to the mixture was added a solution of methanesulfonic anhydride (880mg) in THF (5.0m1), at room temperature. The mixture was stirred at room temperature for 37.5 hours, diluted with ethyl acetate, and washed with water, 1N hydrochloric acid, water and saturated brine, and the organic layer was dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give crystals, which were washed with ethyl acetate/hexane to give methyl 7-(4-ethoxy-3-fluorophenyl)-1-methylsulfonyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (193mg ) as white crystals.

The mother liquor was concentrated, and the residue was purified with silica gel column chromatography (15g, hexane . ethyl acetate = 3 . 1) to give desired product.
The obtained methyl 7-(4-ethoxy-3-fluorophenyl)-1-methylsulfonyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate was collected and dissolved in a mixture of THF and ethanol (1 . 1, v/v, 10.0m1). To the solution was added 1N sodium hydroxide solution (3.6m1), and the mixture was stirred at room temperature for 16.5 hours. The mixture was a little concentrated, and to the residue was added 1N hydrochloric acid to convert weakly acidic solution.
The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give crystals, which were washed with ethyl acetate/hexane to give 7-(4-ethoxy-3-fluorophenyl)-1-methylsulfonyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (213mg, 52~) as white crystals.
mp 237 - 239°C.
1H-NMR (200 MHz, DMSO-d6) 8 1.38 (3H, t, J = 7. 0 Hz) , 2. 90 (2H, t, J = 5.4 Hz), 3.09 (3H, s), 3.70 (2H, t, J = 4.8 Hz), 4 . 16 (2H, q, J = 7. 1 Hz) , 7. 23 (1H, d, J = 8 . 9 Hz) , 7 . 50 -7.56 (2H, m) , 7. 63 - 7.71 (2H, m) , 7.76 (1H, s) , 7. 94 (1H, d, J = 1.6 Hz).

IR (KBr) 1686, 1669, 1622, 1499, 1350, 1271, 1150, 970, 801, 783 cm 1.
Anal. Calcd. for CZOH2oFNO5S (0.3H20 additive) : C, 58.47; H, 5.05; N, 3.41. Found C, 58.50; H, 4.94; N, 3.44.
Reference Example 78 In a mixture of THF and ethanol (1 . 1, v/v, 20.0m1 ) was dissolved methyl 7-(4-ethoxy-3-fluorophenyl)-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (441mg). To the solution was added 1N sodium hydroxide solution (12.0m1), and the mixture was stirred at room temperature for 16 hours. The mixture was a little concentrated, and to the residue was added 1N
hydrochloric acid to convert weakly acidic solution. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give crystals, which were washed with ethyl acetate/hexane to give 7-(4-ethoxy-3-fluorophenyl)-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (435mg) as white crystals.
mp 220 - 222°C.
1H-NMR (200 MHz, DMSO-d6) 8 1.37 (3H, t, J = 7.0 Hz) , 2.74 (2H, t-like) , 3. 71 (2H, t-like) , 4. 16 (2H, q, J = 6. 9 Hz) , 7.24 (1H, t, J = 8.8 Hz), 7.41 (1H, d, J = 8.4 Hz), 7.53 -7.58 (1H, m) , 7. 65 - 7.75 (3H, m) , 7. 99 (1H, d-like) , 8. 53 (1H, s) .
IR (KBr) 1705, 1655, 1499, 1362, 1304, 1292, 1273, 1231, 1217, 1196, 1134, 816 cm 1.
Anal. Calcd. for CZOH18FN04 (0.2H20 additive) : C, 66.92; H, 5.17: N, 3.90. Found C, 66.80; H, 5.28; N, 3.81.
Reference Example 79 In a mixture of water . ethanol . toluene (1 . 1 .
10, v/v, 36.0m1) were dissolved 4-[(2-methylthio)ethoxy]phenyl borate (760mg) and methyl 7-bromo-1-(t-butoxycarbonyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (1141mg). To the solution was added potassium carbonate (990mg), and the mixture was stirred under argon atmosphere at room temperature for 30 minutes.
To the mixture was added tetrakistriphenylphosphinepalladium (138mg) and the mixture was heated to reflux under argon atmosphere for 10 hours. The mixture was diluted with ethyl acetate, and washed with water and saturated brine, and the organic layer was dried with anhydrous magnesium sulfate.
The solvent was evaporated under reduced pressure, and the residue was purified with silica gel column chromatography (50g, hexane . ethyl acetate = 9 . 1 4 . 1) to give methyl 1-(t-butoxycarbonyl)-7-[4-(2-methylthio)ethoxyphenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (1370mg, 98$) as white crystals.

mp 142.5 - 143.5°C.
1H-NMR (200 MHz, CDC13) 8 1.50 (9H, s), 2.24 (3H, s), 2.89 2.95 (4H, m), 3.63 - 3.70 (2H, br), 3.84 (3H, s), 4.21 (2H, t, J = 6.8 Hz), 6.99 (2H, d, J = 8.8 Hz), 7.46 - 7.58 (5H, m), 7.74 (1H, s).
IR (KBr) 1703, 1497, 1391, 1238, 1163 cm 1.
Anal. Calcd. for Cz6H31NO5S: C, 66.50 H, 6.65: N, 2.98.
Found C, 66.27; H, 6.68; N, 3.04.
Reference Example 80 In ethyl acetate (80m1) was dissolved methyl 1-(t-butoxycarbonyl)-7-[4-(2-methylthio)ethoxyphenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (1320mg). To the solution was added 1N hydrochloric acid (15m1) at room temperature, and the mixture was stirred at 90°C for 1.5 hours and neutralized with 1N sodium hydroxide and saturated sodium hydrogen carbonate solution. To the mixture was added ethyl acetate, and the separated organic layer was washed with saturated sodium hydrogen carbonate solution, water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give crystals, which were washed with ethyl acetate/hexane to give methyl 7-[4-(2-methylthio)ethoxyphenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (910mg) as yellow crystals.
The mother liquor was concentrated under reduced pressure, . CA 02380860 2001-12-03 and the residue was purified with silica gel column chromatography (20g, hexane . ethyl acetate = 4 . 1) to give methyl 7-[4-(2-methylthio)ethoxyphenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (910mg) as yellow crystals.
Yield, 1020mg (980).
mp 114.5 - 117C.

1H-NMR (200 MHz, CDC13) 8 2.24 9 (2H,t, =
(3H, s), 2.8 J 4.2 Hz), 2.91 (2H, t, J = 6.8 Hz), 3.41 (2H, t, - 4.7 Hz), J

3.81 (3H, s), 4.20 (2H, t, J = 6.9 Hz), 4.63 4.72 (1H, -br), 6.68 (1H, d, J = 8.4 Hz), 6.96 (2H, d, = 8.8 Hz), J

7.32 (1H, dd, J = 8.2, 2.2 Hz), 7.46 (1H, d, = 2.6 Hz), J

7.47 (2H, d, J = 8.8 Hz), 7 .73 (1H, s).

IR (KBr) 3380, 1698, 1609, 1499, 1269, 4, 124 1209, cm Anal. Calcd. for CZIHasNO3S: C, 68.27; H, 6.27; N, 3.79.

Found C, 68.16; H, 6.22; N, 3.75.

Reference Example 81 To anhydrous acetic acid (0.65m1) was added formic acid (0.32m1) at 0°C, and the mixture was stirred at 55°C
for 2 hours, air-cooled and diluted with THF (10m1). In THF (15m1) was dissolved methyl 7-[4-(2-methylthio)ethoxyphenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (565mg), and the solution was added dropwise to the previously prepared solution of formic anhydride in THF, at 0°C. The mixture was stirred at room temperature for 2 hours, and the solvent was evaporated under reduced pressure. The residue was diluted with ethyl acetate, washed with saturated sodium hydrogen carbonate solution, water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give crystals, which were washed with ethyl acetate/hexane to give methyl 1-formyl-7-[4-(2-methylthio)ethoxyphenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (578mg, 95~) as white crystals.
mp 160 - 162°C.
1H-NMR (200 MHz, CDC13) 8 2.24 (3H, s), 2.93 (2H, t, J = 6.7 Hz), 2.95 (2H, t, J = 4.6 Hz), 3.83 - 3.88 (2H, m), 3.84 (3H, s), 4.22 (2H, t, J - 6.8 Hz), 6.97 - 7.04 (2H, m), 7.18 (1H, d, J = 8.2 Hz), 7.49 - 7.55 (2H, m), 7.56 (1H, dd, J = 8.2, 2.2 Hz), 7.68 (1H, d, J = 1.8 Hz), 7.76 (1H, s), 8.53 (1H, s).
IR (KBr) 1705, 1673, 1607, 1497, 1435, 1358, 1236, 1192, 824 cm 1.
Anal. Calcd. for CZZH2sNO4S: C, 66.48; H, 5.83; N, 3.52.
Found C, 66.23; H, 5.93; N, 3.41.
Reference Example 82 In THF (10.0m1) were dissolved methyl 7-[4-(2-methylthio)ethoxyphenyl]-2,3-dihydro-1-benzazepine-4-carboxylate (374mg) and pyridine (0.82m1). To the solution was added a solution of methanesulfonic anhydride (882mg) in THF (5.0m1), at room temperature, and the mixture was stirred at 50°C for 13 hours. The mixture was diluted with ethyl acetate. and washed with water, 1N hydrochloric acid, water and saturated brine, and the organic layer was dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified with silica gel column chromatography (25g, hexane . ethyl acetate = 4 .
1 ~ 1 . 1) to give crystals, which were washed with ethyl acetate/hexane to give methyl 1-methylsulfonyl-7-[4-(2-methylthio)ethoxyphenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (201mg, 44~) as white crystals.
mp 157 - 159C.

1H-NMR (200 MHz, CDC13) 8 2 .24 (3H, s), 2.78 (3H, s), 2.92 (2H, t, J = 6.8 Hz), 3.05 (2H,td-like, J 5.4 Hz (t)), -3.86 (3H, s), 3.87 (2H, t, J 5.9 Hz), 4.22 J
= (2H, t, =

6.7 Hz), 7.00 (2H, d, J - 8.8 Hz), 7.49 - 7.57 (3H,m), 7.64 (1H, d, J = 2.0 Hz), 7.68(1H, d, J = 8.4 Hz), 7.81 (1H, s) .
IR (KBr) 1709, 1493, 1343, 1248, 1155 cml.
Anal. Calcd. for CZZHzsNOssz: C, 59.04; H, 5.63; N, 3.13.
Found C, 58.91; H, 5.65 N, 3.08.
Reference Example 83 In a mixture of THF and ethanol (1 . 1, v/v, 40.0m1) was dissolved methyl 1-formyl-7-[4-(2-methylthio)ethoxyphenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (531mg). To the solution was added 1N sodium hydroxide solution (13.5m1), and the mixture was stirred at room temperature for 14 hours. The mixture was a little concentrated, and to the residue was added 1N hydrochloric acid to convert weakly acidic solution. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give crystals, which were washed with ethyl acetate/hexane to give 1-formyl-7-[4-(2-methylthio)ethoxyphenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (470mg, 920) as white crystals.
mp 199 - 201°C.
1H-NMR (200 MHz, DMSO-d6) 8 2.18 (3H, s), 2.76 (2H, t-like), 2.87 (2H, t, J = 6.6 Hz), 3.72 (2H, t-like), 4.21 (2H, t, J
- 6.2 Hz), 7.04 (2H, d, J = 8.8 Hz), 7.40 (1H, d, J = 8.8 Hz), 7.67 - 7.74 (4H, m), 7.91 (1H, s), 8.53 (1H, s).
IR (KBr) 1688, 1671, 1501, 1422, 1364, 1292, 1256, 1194, 1182, 1019, 822 cm 1.
Anal. Calcd. for CZ1H21NO9S: C, 65.78; H, 5.52: N, 3.65.
Found C, 65.49; H, 5.62; N, 3.58.
Reference Example 84 In a mixture of THF and ethanol (1 . 1, v/v, 20.0m1) was dissolved methyl 1-methylsulfonyl-7-[4-(2-methylthio)ethoxyphenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (169mg). To the solution was added 1N sodium hydroxide solution (5.5m1), and the mixture was stirred at room temperature for 14 hours. The mixture was a little concentrated, and to the residue was added 1N
hydrochloric acid to convert weakly acidic solution. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give crystals, which were washed with ethyl acetate/hexane to give 1-methylsulfonyl-7-[4-(2-methylthio)ethoxyphenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (157mg, 96~) as white crystals.
mp 234 - 239°C (dec. ) .
1H-NMR (200 MHz, DMSO-d6) 8 2. 17 (3H, s) , 2.87 (2H, t, J =
6.6 Hz), 2.90 (2H, t-like), 3.08 (3H, s), 3.70 (2H, t-like), 4.21 (2H, t, J = 6.6 Hz), 7.05 (2H, d, J = 8.8 Hz), 7.51 (1H, d, J = 8.0 Hz), 7.61 - 7.75 (4H, m), 7.86 (1H, d-like).
IR (KBr) 1669, 1495, 1437, 1343, 1271, 1250, 1240, 1144, 824, 517 cm 1.
Anal. Calcd. for CzlH2sNOsSz: C, 58.18: H, 5.35: N, 3.23.
Found C, 58.39 H, 5.39 N, 3.17.
Reference Example 85 In a mixture of water . ethanol . toluene (1 . 1 .
10, v/v, 42.0m1) were dissolved 4-(2-propoxy)ethoxyphenyl borate (920mg) and methyl 7-bromo-1-(t-butoxycarbonyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (1308mg). To the solution was added potassium carbonate (1135mg), and the mixture was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (119mg), and the mixture was heated to reflux under argon atmosphere for 14.5 hours. The mixture was diluted with ethyl acetate, and washed with water and saturated brine, and the organic layer was dried with anhydrous magnesium sulfate.
The solvent was evaporated under reduced pressure. and the residue was purified with silica gel column chromatography (50g, hexane . ethyl acetate = 9 . 1 --3 . 1) to give methyl 1-(t-butoxycarbonyl)-7-[4-(2-propoxy)ethoxyphenyl]-2.3-dihydro-1H-1-benzazepine-4-carboxylate (1536mg, 930) as colorless oil.
1H-NMR (200 MHz, CDC13) 8 0.95 (3H, t, J = 7.4 Hz), 1.49 (9H, s), 1.66 (2H, sextet, J = 7.1 Hz), 2.91 (2H, t, J = 4.7 Hz), 3.52 (2H, t, J = 6.7 Hz), 3.55 - 3.82 (2H, br), 3.82 (2H, t, J = 4.9 Hz), 3.83 (3H, s), 4.18 (2H, t, J = 4.9 Hz), 7.01 (2H, d, J = 8.8 Hz), 7.45 - 7.58 (5H, m), 7.74 (1H, s).
IR (KBr) 1705, 1497, 1391, 1287, 1236, 1163, 1086 cm 1.
Reference Example 86 ' CA 02380860 2001-12-03 In ethyl acetate (80m1) was dissolved methyl 1-(t-butoxycarbonyl)-7-[4-(2-propoxy)ethoxyphenyl]-2.3-dihydro-1H-1-benzazepine-4-carboxoylate (1536mg). To the solution was added 1N hydrochloric acid (20m1) at room temperature, and the mixture was stirred at 90°C for 1 hour and neutralized with saturated sodium hydrogen carbonate solution, and to the mixture was added ethyl acetate. The separated organic layer was washed with saturated sodium hydrogen carbonate solution, water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give crystals, which were washed with ethyl acetate/hexane to give methyl 7-[4-(2-propoxy)ethoxyphenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (523mg) as yellow crystals. The mother liquor was concentrated under reduced pressure, and the residue was purified with silica gel column chromatography (65g, hexane . ethyl acetate = 3 . 1) to give methyl 7-[4-(2-propoxy)ethoxyphenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (606mg) as yellow crystals.
Yield, 1129mg (93$).
mp 86 - 88°C.
1H-NMR (200 MHz, CDC13) 8 0.94 (3H, t, J = 7.4 Hz), 1.65 (2H, sextet, J = 7.2 Hz), 2.89 (2H, t, J = 4.5 Hz), 3.40 (2H, brs ) , 3 . 51 ( 2H, t, J = 6 . 8 Hz ) , 3 . 81 ( 3H, s and 2H, t, J =

4.9 Hz), 4.16 (2H, t, J = 5.0 Hz), 4.60 (1H, brs), 6.67 (1H, d, J = 8.4 Hz), 6.95 - 7.01 (2H, m), 7.32 (1H, dd, J = 8.2, 2.2 Hz), 7.42 - 7.48 (2H, m), 7.46 (1H, d, J - 2.0 Hz), 7.73 (1H, s).
IR (KBr) 3380, 1698, 1611, 1501, 1269, 1246, 1209, 1177, 820 cm 1.
Anal. Calcd. for Cz3H2~N09: C, 72.42; H, 7.13; N, 3.67. Found C, 72.28; H, 7.09; N, 3.73.
Reference Example 87 To anhydrous acetic acid (0.51m1) was added formic acid, (0.25m1) at 0°C, and the mixture was stirred at 55°C
for 2 hours, air-cooled and diluted with THF (lOml). In THF (15m1) was dissolved methyl 7-[4-(2-propoxy)ethoxyphenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (462mg), and the solution was added dropwise to the previously prepared solution of formic anhydride in THF, at 0°C. The mixture was stirred at room temperature for 2 hours, and the solvent was evaporated under reduced pressure. The residue was diluted with ethyl acetate, washed with saturated sodium hydrogen carbonate solution, water and saturated brine, and dried with anhydrous, magnesium sulfate. The solvent was evaporated under reduced pressure to give crystals, which were washed with ethyl acetate/hexane to give methyl 1-formyl-7-[4-(2-propoxy)ethoxyphenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (496mg) as white crystals.
mp 107 - 108°C.
1H-NMR (200 MHz, CDC13) 8 0.95 (3H, t, J = 7.3 Hz), 1.62 (2H, sextet, J = 7.2 Hz), 2.95 (2H, t, J = 4.7 Hz), 3.52 (2H, t, J = 6.7 Hz), 3.80 - 3.88 (4H, m), 3.84 (3H, s), 4.18 (2H, t, J = 4.9 Hz), 7.03 (2H, d, J = 8.8 Hz), 7.17 (1H, d, J = 8.0 Hz) , 7.51 (2H, d, J = 8. 8 Hz) , 7.56 (1H, dd, J = 8. 0, 2.2 Hz), 7.68 (1H, d, J = 1.8 Hz), 7.75 (1H, s), 8.53 (1H, s).
IR (KBr) 1709, 1678, 1360, 1291, 1236, 1192, 824 cml.
Anal. Calcd. for C24H2,N05: C, 70.40; H, 6.65; N, 3.42. Found C, 70.37; H, 6.64; N, 3.41.
Reference Example 88 In THF (20.0m1) were dissolved methyl 7-[4-(2-propoxy)ethoxyphenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (600mg) and pyridine (1.53m1). To the solution was added a solution of methanesulfonic anhydride (1.64g) in THF (lO.Oml), at room temperature, and the mixture was stirred at 50°C for 14.5 hours. The mixture was diluted with ethyl acetate, and washed with water, 1N hydrochloric acid, water and saturated brine, and the organic layer was dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified with silica gel column chromatography (35g, hexane . ethyl acetate = 4 .
1 ~ 2:1) to give crystals, which were washed with ethyl acetate/hexane to give methyl 1-methylsulfonyl-7-[4-(2-propoxy)ethoxyphenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (231mg) as white crystals. The mother liquor was concentrated under reduced pressure, and the residue was purified with silica gel column chromatography (3508, hexane . ethyl acetate = 3 . 1 -~ 2 . 1) to give methyl 1-methylsulfonyl-7-[4-(2-propoxy)ethoxyphenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (170mg) as white crystals.
Yield, 402mg (56~).
mp 119 - 121°C .
1H-NMR (200 MHz, CDC13) 8 0.95 (3H, t, J = 7.4 Hz), 1.65 (2H, sextet, J = 7.3 Hz), 2.78 (3H, s), 3.05 (2H, t, J = 5.5 Hz), 3.52 (2H, t, J = 6.8 Hz), 3.80 - 3.89 (4H, m), 3.85 (3H, s), 4.18 (2H, t, J = 5.0 Hz), 7.02 (2H, d, J = 8.8 Hz), 7.51 ( 2H, d, J = 8 . 8 Hz ) , 7 . 54 ( 1H, dd, J = 8 . 4, 2 . 2 Hz ) , 7 . 63 (1H, d, J = 1.8 Hz), 7.67 (1H, d, J = 8.4 Hz), 7.80 (1H, s).
IR (KBr) 1709, 1493, 1345, 1289, 1248, 1188, 1155, 1132, 1103 cm 1.
Anal. Calcd. for CZQHZ9N06S (0.4H20 additive) : C, 61.76; H, 6.44; N, 3.00. Found C, 61.61; H, 6.22; N, 2.96.
Reference Example 89 In a mixture of THF and ethanol (1 . l, v/v, 30.0m1) was dissolved methyl 1-formyl-7-[4-(2-propoxy)ethoxyphenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (445mg). To the solution was added 1N sodium hydroxide solution (11.0m1), and the mixture was stirred at room temperature for 13 hours. The mixture was a little concentrated, and to the residue was added 1N
hydrochloric acid to convert weakly acidic solution. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give crystals, which were washed with ethyl acetate/hexane to give 1-formyl-7-[4-(2-propoxy)ethoxyphenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (430mg) as white crystals.
mp 165 - 166°C.
1H-NMR (200 MHz, DMSO-d6) 8 0. 88 (3H, t, J = 7.5 Hz) , 1.54 (2H, sextet, J = 7.1 Hz), 2.75 (2H, t-like), 3.43 (2H, t, J
- 6.8 Hz) , 3.72 (4H, t, J = 4. 6 Hz) , 4. 15 (2H, t, J = 4. 6 Hz), 7.04 (2H, d, J = 8.8 Hz), 7.40 (1H, d, J = 8.0 Hz), 7.69 (2H, d, J = 8.8 Hz), 7.67 - 7.74 (2H, m), 7.92 (1H, d, J = 1.8 Hz), 8.53 (1H, s).
IR (KBr) 1682, 1499, 1360, 1291, 1258, 1246, 1192, 1130, 820 cm 1.
Anal. Calcd. for CZ3HzsNOs: C, 69.86; H, 6.37; N, 3.54. Found C, 69.69; H, 6.38; N, 4.59.
Reference Example 90 In a mixture of THF and ethanol (1 . 1, v/v, 30.0m1) was dissolved methyl 1-methylsulfonyl-7-[4-(2-propoxy)ethoxyphenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (354mg). To the solution was added 1N sodium hydroxide solution (7.7m1), and the mixture was stirred at room temperature for 15.5 hours. The mixture was a little concentrated, and to the residue was added 1N
hydrochloric acid to convert weakly acidic solution. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give crystals, which were washed with ethyl acetate/hexane to give 1-methylsulfonyl-7-[4-(2-propoxy)ethoxyphenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (337mg, 98s) as white crystals.
mp 213 - 215°C.
1H-NMR (200 MHz, DMSO-d6) 8 0.88 (3H, t, J = 7.3 Hz) , 1.54 ( 2H, sextet, J = 7 . 0 Hz ) , 2 . 50 ( 3H, s ) , 3 . 33 ( 2H, t-like ) , 3.43 (2H, t, J = 6. 6 Hz) , 3.72 (4H, t-like) , 4. 15 (2H, t-like) , 7. 04 (2H, d, J = 8. 8 Hz) , 7. 51 (1H, d, J = 8. 0 Hz) , 7.63 - 7.75 (4H, m), 7.88 (1H, s).
IR (KBr) 1669, 1493, 1341, 1294, 1271, 1250, 1154, 1128, 785, 519 cm 1.
Anal. Calcd. for C23Hz~N06S (O.lHzO additive) : C, 61.75; H, 6.13; N, 3.13. Found C, 61.50; H, 5.88; N, 3.01.

Reference Example 91 In THF (1000m1) was dissolved 4-[[N-(benzyloxy)carbonyl]amino]butyric acid (50.0g). To the solution were added propyl bromide (77.5g) and sodium iodide (94.4g), and to the mixture was gradually added at -5°C 60% sodium hydride (25.2g). Under nitrogen atmosphere, the mixture was stirred at 0°C for 15 minutes and then at 75°C for 4 days. The mixture was concentrated under reduced pressure, and to the residue was added water. The aqueous layer was adjusted to pHll with sodium hydroxide (granule) and washed with ether (twice). The aqueous layer was adjusted to pH2 with concentrated hydrochloric acid and washed with ethyl acetate (thrice). The organic layer was washed with 1M
sodium thiosulfate solution and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 4-[[N-(benzyloxy)carbonyl]-N-propylamino]butyric acid (35.88, 61%).
1H-NMR (200 MHz, CDC13) 8 0.88 (3H, t, J = 7.3 Hz) , 1.50 -1.57 (2H, m), 1.85 - 1.90 (2H, m), 2.34 - 2.41 (2H, m), 3.17 - 3.30 (4H, m), 5.13 (2H, s), 7.35 (5H, s).
Reference Example 92 To 4-[[N-(benzyloxy)carbonyl]-N-propylamino]butyric acid (35.8g) was added t-butanol (350m1), and then was added di-t-butyl dicarbonate (140g). To the mixture was added dimethylaminopyridine (4.69g), and the mixture was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure, and the residue was purified with silica gel column chromatography to give pale yellow oil of t-butyl 4-[[N-(benzyloxy)carbonyl]-N-propylamino]butyrate (23.8g, 55~).
1H-NMR (200 MHz, CDC13) 8 0.88 (3H, t, J = 7.3 Hz), 1.45 (9H, s) , 1. 52 - 1. 59 (2H, m) , 1. 81 - 1. 84 (2H, m) , 2.23 (2H, t, J = 7. 1 Hz) , 3. 17 - 3.27 (4H, m) , 5.13 (2H, s) , 7. 35 (5H, s) .
IR (KBr) 2969, 1728, 1703, 1476, 1456, 1422, 1368, 1242, 1155, 1136 cm 1.
Reference Example 93 In methanol (250m1) was dissolved t-butyl 4-[[N-(benzyloxy) carbonyl]-N-propylamino] butyrate (23.7g), and to the solution was added 10~ palladium on carbon (2.37g). The mixture was stirred under hydrogen atmosphere at room temperature for 2 hours, and 10~
palladium on carbon was removed. The solvent was evaporated under reduced pressure to give colorless oil of t-butyl 4-propylaminobutyrate [16.88 (containing methanol)].
1H-NMR (200 MHz, CDC13) b 0.92 (3H, t, J = 7.1 Hz), 1.45 (9H, s) , 1.47 - 1. 67 (4H, m) , 1. 70 - 1.85 (2H, m) , 2.25 (2H, q, ~

J = 7.9 Hz), 2.60 (2H, dt, J = 11.6, 7.2 Hz), 3.21 (1H, m).
IR (KBr) 2967, 2936, 1728, 1480, 1456, 1424, 1368, 1246, 1155 cm 1.
Reference Example 94 To a solution of t-butyl 4-propylaminobutyrate (14.28, 70.7mmo1) in DMF (20m1) were added 5-bromo-2-fluorobenzaldehyde (14.48, 70.9mmo1) and potassium carbonate (14.78, 106mmo1) at room temperature, and the mixture was stirred at 80°C for 94 hours. The mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified with silica gel column chromatography (hexane . ethyl acetate = 10 . 1) to give yellow oil of t-butyl 4-(4-bromo-2-formylphenyl)propylaminobutyrate (14.28, 52~).
1H-NMR (200 MHz, CDC13) 8 0.84 (3H, t, J = 7.8 Hz), 1.45 (9H, s), 1.42 - 1.63 (2H, m), 1.81 (2H, quint, J = 7.4 Hz), 2.19 (2H, t, J = 7.5 Hz), 3.09 (2H, t, J = 7.6 Hz), 3.17 (2H, t, J = 7.5 Hz) , 7.06 (1H, d, J = 8. 8 Hz) , 7. 56 (1H, dd, J =
8.7, 2.5 Hz), 7.90 (1H, d, J = 2.6 Hz), 10.24 (1H, s).
IR (KBr) 2971, 1730, 1694, 1480, 1368, 1244, 1157 cm 1.
Reference Example 95 In a mixture of t-butanol and toluene (1:10, v/v, 440m1) was dissolved t-butyl 4-(4-bromo-2-formylphenyl)propylbutyrate (14.1g). To the solution was added sodium t-butoxide (5.29g) at room temperature, and the mixture was heated to reflux for 1 hour (90°C), air-cooled, diluted with ethyl acetate, washed with water, 0.5N sodium hydroxide solution, water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified with silica gel column chromatography (hexane . ethyl acetate = 4 . 1) to give yellow oil of t-butyl 7-bromo-1-propyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (8.07g, 60$).
1H-NMR (200 MHz, CDC13) 8 0.95 (3H, t, J = 7.5 Hz), 1.53 (9H, s), 1.68 (2H, sextet, J = 7.6 Hz), 2.75 (2H, t, J = 4.4 Hz), 3.18 - 3.26 (4H, m), 6.67 (1H, d, J = 9.2 Hz), 7.22 (1H, dd, J = 8.8, 2.6 Hz), 7.39 (1H, d, J = 2.6 Hz), 7.46 (1H, s).
IR (KBr) 2969, 1698, 1497, 1368, 1269, 1254, 1159 cm 1.
Reference Example 96 In ethyl acetate (80m1) was dissolved t-butyl 7-bromo-1-propyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (8.05g). To the solution was added a solution of 4N
hydrochloric acid in ethyl acetate (80m1), and the mixture was stirred at room temperature for 12 hours. To the mixture was added water, and the mixture was adjusted to pH2 with saturated sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue of solid was washed with hexane-ethyl acetate to give yellow crystals of 7-bromo-1-propyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (2.61g, 39~).
mp 172 - 173°C.
1H-NMR (200 MHz, CDC13) 8 0.95 (3H, t, J = 7.3 Hz), 1.70 (2H, sextet, J = 7.5 Hz), 2.81 (2H, t, J = 4.6 Hz), 3.22 - 3.29 (4H, m), 6.70 (1H, d, J = 8.8 Hz), 7.25 (1H, dd, J = 8.8, 2.6 Hz), 7.43 (1H, d, J = 2.0 Hz), 7.69 (1H, s).
IR (KBr) 2963, 1674, 1497, 1410, 1277, 1171 cml.
Anal. Calcd. for C14H16BrN02: C, 54.21; H, 5.20; N, 4.52.
Found C, 54.17; H, 5.05: N, 4.42.
Reference Example 97 In DMF (12m1) was dissolved 7-bromo-1-propyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (2430mg, 7.83mmo1). To the solution was added thionyl chloride (1.4m1), and the mixture was stirred at room temperature for 30 minutes. The solvent was evaporated under reduced pressure, and the residue was suspended in THF (50m1).
To 4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]aniline dihydrochloride (2757mg) was added THF (40m1), and to the mixture was added dropwise triethylamine (8.2m1). The mixture was stirred at room temperature for 30 minutes, and to the mixture was added dropwise the previously prepared acid chloride suspension in THF, at 0°C. The mixture was stirred at room temperature for 21 hours, and the mixture was concentrated. To the mixture was added ethyl acetate, and the mixture was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified with silica gel column chromatography (ethyl acetate -~ ethyl acetate: ethanol=10:1) and recrystallized from ethyl acetate-hexane to give yellow crystals of 7-bromo-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-1-propyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (3219mg, 80$).
mp 134 - 136°C.
1H-NMR (200 MHz, CDC13) 8 0. 97 (3H, t, J = 7. 5 Hz) , 1. 60 -1.80 (6H, m) , 2.21 (3H, s) , 2.57 - 2.70 (1H, m) , 2. 89 (2H, t, J = 4.6 Hz), 3.22 - 3.30 (4H, m), 3.37 (2H, td, J = 11.1, 2. 8 Hz) , 3. 57 (2H, s) , 4. O1 - 4. 07 (2H, m) , 6. 71 (1H, d, J
- 9.2 Hz), 7.19 (1H, s), 7.24 (1H, dd, J = 9.0, 2.6 Hz), 7. 30 (2H, d, J = 8. 4 Hz) , 7.41 (1H, d, J = 2. 6 Hz) , 7.50 ( 1H, s ) , 7 . 52 ( 2H, d, J = 8 . 4 Hz ) .
IR (KBr) 2957, 1645, 1597, 1514, 1497, 1406, 1314, 1246, 1173 cm 1.
Anal. Calcd. for Cz,H34BrN302: C, 63.28; H, 6.69 N, 8.20.
Found C, 63.19 H, 6.54; N, 8.05.

Working Example 1 (Production of Compound 1) In DMF (lOml) was dissolved 7-[4-(2-ethoxyethoxy)phenyl]-1-formyl-2,3-dihydro-1H-1-benzazepine-9-carboxylic acid (0.18g). To the solution was added, under ice-cooling, thionyl chloride (0.09m1), and the mixture was stirred at room temperature for 30 minutes. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in THF (20m1).
The solution was added dropwise to a solution of 4-[N-methyl-N-(tetrahydro-2H-pyran-4-yl)aminomethyl]aniline (0.12g) and triethylamine (0.33m1) in THF (lOml), under ice-cooling, and the mixture was stirred under nitrogen atmosphere at room temperature overnight. Under reduced pressure, the solvent was evaporated. To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated to give crude crystals, which were recrystallized from ethyl acetate/hexane to give 7-[4-(2-ethoxyethoxy)phenyl]-1-formyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxalnide (Compound 1) (0.23g) as colorless crystals.
mp 192 - 194°C.

1H-NMR (8 ppm, CDC13) 1.26 (3H, t, J = 1.
7.0 Hz) , 1.59 - 75 ( 4H, m) , 2 . 21 ( 3H, s ) , 2 . 59 - m) , 3 . 02 t, 2 . 70 ( 1H, ( 2H, J

- 5.1 Hz) , 3.37 (2H, dt, J = 1.5, 11.4 Hz), 3.57 (2H, s), 3. 63 (2H, q, J = 7. 0 Hz) , 3. 83 (2H, J = 4. 8 Hz) 3.
t, , 91 (2H, t, J ) , 4 . 18 (2H,J
= 5. 1 Hz) t, =
, 4 . 01 -4 . 07 (2H, m 4.8 Hz), 7.02 (2H, d, J = 8.8 Hz), 7.18 (1H, d, J = Hz), 8.4 7.31 (2H, d, J = 8.4 Hz), 7.45 - 7.57 (6H, m), 7.65 (1H, br), 7.66 (1H, d, J = 1.8 Hz), 8.54 (1H, s).

IR (KBr) v: 3297, 2946, 2847, 1669 ciril.

Anal. Calcd. H, 7.08; N, .20.
for C35H91N305: 7 C, 72.02;

Found C, 71.90; H, 6.79; N, 7.05.

Working Example 2 (Production of Compound 2) In DMF (5m1) was dissolved 7-[4-(3-ethoxypropoxy)phenyl]-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.25g). To the solution was added, under ice-cooling, thionyl chloride (0.12m1), and the mixture was stirred at room temperature for 30 minutes. Under reduced pressure, the solvent was evaporated, and the residue was suspended in THF (15m1).
The suspension was added dropwise to a solution of 4-[N-methyl-N-(tetrahydro-2H-pyran-4-yl)aminomethyl)aniline (0.16g) and triethylamine (0.44m1) in THF (5m1), under ice-cooling, and the mixture was stirred under nitrogen atmosphere at room temperature overnight. Under reduced pressure, the solvent was evaporated. To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated to give crude crystals, which were recrystallized from ethyl acetate/hexane to give 7-[4-(3-ethoxypropoxy)phenyl]-1-formyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 2) (0.29g) as colorless crystals.
mp 166 169C.
-1H-NMR ppm, CDC13) 1.22(3H, t, J = 7.0 Hz) 1. 64 - 1.82 (8 , (4H, m), 2.02 - 2.15 (2H,m), 0 - 2.68 2.21 (1H, (3H, s), 2.6 m), 3.03 (2H, t, J 5.5 Hz), 3.37 (2H, dt, = 2.6, 11.2 = J

Hz) , 3.46 - 3. 66 (6H,m) 3. (2H, t, J = 5.5 Hz) , 4.02 , 92 -4.07 (2H, m), 4.13 2H, t, = 6.3 Hz), 7.01 (2H, d, J
( J =

8.8 Hz), 7.19 (1H, J 8.2 J = 8.6 Hz), d, = Hz), 7.32 (2H, d, 7.47 - 60 (6H, m), 7.68(1H, d, J = 2.0 Hz), 8.55 (1H, 7. s).

IR (KBr) v: 2946, 2849, 1669 cml.
Anal. Calcd. for C36H93N3~5~ C. 72.34; H, 7.25; N, 7.03.
Found C, 72.54; H, 7.11; N, 7.00.
Working Example 3 (Production of Compound 3) In DMF (5m1) was dissolved 7-[4-(2-butoxyethoxy)phenyl]-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.23g). To the solution was added, under ice-cooling, thionyl chloride (O.llml), and the mixture was stirred at room temperature for 30 minutes. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in THF (25m1).
The solution was added dropwise a solution of 4-[N-methyl-N-(tetrayhydro-3H-pyran-4-yl)aminomethyl]aniline (0.15g), and triethylamine (0.4m1) in THF (5m1), under ice-cooling, and the mixture was stirred under nitrogen atmosphere at room temperature overnight. Under reduced pressure, the solvent was evaporated. To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated to give crude crystals, which were recrystallized from ethanol to give 7-[4-(2-butoxyethoxy)phenyl]-1-formyl-N-[[4-[(N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino)methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 3) (0.23g) as colorless crystals.
mp 171 - 173°C.
1H-NMR (8 ppm, CDC13) 0. 94 (3H, t, J = 7.2 Hz) , 1.31 - 1.49 (2H, m), 1.55 - 1.65 (2H, m), 1.70 - 1.75 (4H, m), 2.21 (3H, s) , 2. 60 - 2.71 (1H, m) , 3. 04 (2H, t, J = 5.5 Hz) , 3.37 (2H, dt, J = 3.2, 11. 3 Hz) , 3. 53 - 3. 59 (4H, m) , 3. 82 (2H, t, J
- 4 . 9 Hz ) , 3 . 92 ( 2H, t, J = 5 . 5 Hz ) , 4 . O1 - 4 . 07 ( 2H, m) , 4. 18 (2H, t, J = 4. 9 Hz) , 7.03 (2H, d, J - 8. 8 Hz) , 7.19 (1H, d, J = 8.2 Hz), 7.32 (2H, d, J = 8.4 Hz), 7.46 - 7.56 ( 6H, m) , 7 . 68 ( 1H, d, J = 1. 8 Hz ) , 8 . 55 ( 1H, s ) .
IR (KBr) v: 2940, 1669, 1518, 1497 cml.
Anal. Calcd. for C3,H45N305: C, 72.64; H, 7.41; N, 6.87.
Found C, 72.48; H, 7.11; N, 6.71.
Working Example 4 (Production of Compound 4) In DMF (3.5m1) was dissolved 7-[4-[N-(2-ethoxyethyl)-N-methylamino]phenyl]-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.17g). To the solution was added, under ice-cooling, thionyl chloride (0.08m1), and the mixture was stirred at room temperature for 30 minutes. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in THF (25m1).
The solution was added dropwise to a solution of 4-[N-methyl-N-(tetrahydro-2H-pyran-4-yl)aminomethyl]aniline (O.llg) and triethylamine (0.31m1) in THF (6.5m1), under ice-cooling, and the mixture was stirred under nitrogen atmosphere at room temperature for 1 hour, poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified with silica gel column chromatography (ethyl acetate/ethanol) to give crude crystals, which were recrystallized from ethanol to give 7-[4-[N-(2-ethoxyethyl)-N-methylamino]phenyl]-1-formyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 4) (0.14g) as pale yellow crystals.
mp 157 - 158°C.
1H-NMR (8 ppm, CDC13) 1.21 (3H, t, J = 7.4 Hz) , 1.59 - 1. 82 (4H, m), 2.20 (3H, s), 2.64 (1H, m), 2.96 - 3.06 (2H, m), 3.05 (3H, s), 3.30 - 3.43 (2H, m), 3.52 (2H, q, J = 7.0 Hz), 3.57 (2H, s), 3.56 - 3.63 (2H, m), 3.88 - 3.94 (2H, m), 3.99 - 4.07 (2H, m), 6.80 (2H, d, J = 8.8 Hz), 7.16 (1H, m), 7.29 - 7.56 (7H, m), 7.66 (1H, s), 8.53 (1H, s).
IR (KBr) v: 2946, 2849, 1669, 1609, 1505, 1360, 1316, 1204, 1113, 814 cm 1.
Working Example 5 (Production of Compound 5) In DMF (5m1) was dissolved 7-[4-[N-(2-ethoxyethyl)-N-ethylamino]phenyl]-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.2g). To the solution was added, under ice-cooling, thionyl chloride (0.09m1), and the mixture was stirred at room temperature for 30 minutes. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in THF (25m1).
The solution was added dropwise a solution of 4-[N-methyl-N-(tetrahydro-2H-pyran-4-yl)aminomethyl]aniline (0.20g) and triethylamine (0.35m1) in THF (5m1), under ice-cooling, and the mixture was stirred under nitrogen atmosphere stirred at room temperature overnight. Under reduced pressure, the solvent was evaporated. To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated to give crude crystals, which were recrystallized from ethyl acetate/hexane to give 7-[4-[N-(2-ethoxyethyl)-N-ethylamino]phenyl]-1-formyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 5) (0.23g) as pale yellow crystals.
mp 162 - 164°C.
1H-NMR (8 ppm, CDC13) 1.17 - 1.30 (6H, m), 1.70 - 1.80 (4H, m), 2.21 (3H, s), 2.55 - 2.75 (1H, m), 3.03 (2H, t, J = 5.2 Hz), 3.33 - 3.62 (12H, m), 3.92 (2H, t, J = 5.2 Hz), 4.01 -4.14 (2H, m), 6.78 (2H, d, J - 8.8 Hz), 7.16 (1H, d, J -8.4 Hz), 7.32 (2H, d, J - 8.4 Hz), 7.45 - 7.56 (6H, m), 7.66 (1H, d, J = 2.0 Hz), 8.54 (1H, s).
IR (KBr) v: 2849, 1661, 1609, 1552, 1501 cml.
Anal. Calcd. for C3,H96NQO4~0.2H20: C, 72.33 H, 7.61; N, 9.12.
Found C, 72.30 H, 7.70: N, 9.23.
Working Example 6 (Production of Compound 6) In DMF (7m1) was dissolved 7-[4-[N-ethyl-N-(2-propoxyethyl)amino]phenyl]-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.25g). To the solution w CA 02380860 2001-12-03 was added, under ice-cooling, thionyl chloride (0.11m1), and the mixture was stirred at room temperature for 30 minutes. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in THF (25m1).
The solution was added dropwise to a solution of 4-[N-methyl-N-(tetrahydro-2H-pyran-4-yl)aminomethyl]aniline (0.16g) and triethylamine (0.41m1) in THF (5m1), under ice-cooling, and the mixture was stirred under nitrogen atmosphere at room temperature overnight. Under reduced pressure, the solvent was evaporated. To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated to give crude crystals, which were recrystallized from ethyl acetate/hexane to give 7-[4-[N-ethyl-N-(2-propoxyethyl)amino]phenyl]-1-formyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 6) (0.27g) as pale yellow crystals.
mp 146 - 149°C.
1H-NMR (8 ppm, CDC13) 0 . 93 ( 3H, t, J = 7 . 3 Hz ) , 1. 20 ( 3H, t, J = 6.9 Hz), 1.59 - 1.75 (6H, m), 2.21 (3H, s), 2.55 - 2.75 (1H, m), 3.03 (2H, t, J - 5.4 Hz), 3.31 - 3.61 (12H, m), 3.92 (2H, t, J = 5.4 Hz), 4.01 - 4.14 (2H, m), 6.78 (2H, d, J = 9.2 Hz) , 7.16 (1H, d, J = 8.4 Hz) , 7.32 (2H, d, J = 8.4 Hz), 7.45 - 7.56 (6H, m), 7.66 (1H, d, J - 2.2 Hz), 8.54 (1H, s) .
IR (KBr) v: 2942, 1669 cml.
Anal. Calcd. for C38Hg8N9O4~0.3H20: C, 72.42; H, 7.77; N, 8.89.
Found C, 72.57; H, 7.53; N, 8.59.
Working Example 7 (Production of Compound 7) In THF (15m1) was suspended 7-[4-(2-ethoxyethoxy)phenyl]-1-methanesulfonyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.14g). To the suspension were added, under ice-cooling, thionyl chloride (0.04m1) and DMF (catalytic amount), and the mixture was stirred at room temperature for 1.5 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in THF (15m1). The solution was added dropwise to a solution of 4-[N-methyl-N-(tetrahydro-2H-pyran-4-yl)aminomethyl]aniline (0.08g) and triethylamine (0.14m1) in THF (15m1), under ice-cooling, and the mixture was stirred under nitrogen atmosphere at room temperature for 1 hour. Under reduced pressure, the solvent was evaporated. To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated to give 7-[4-(2-ethoxyethoxy)phenyl]-1-methanesulfonyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 7) (0.15g) as colorless amorphous.
1H-NMR (8 ppm, CDC13) 1.26 (3H, t, J = 7.0 Hz), 1.60 - 1.76 (4H, m), 2.22 (3H, s), 2.67 (1H, br), 2.89 (3H, s), 3.14 ( 2H, t, J = 5 . 2 Hz ) , 3 . 37 ( 2H, dt, J = 3 . 0, 11. 0 Hz ) , 3 . 59 (2H, s), 3.63 (2H, q, J = 7.0 Hz), 3.83 (2H, t, J = 4.8 Hz), 3.92 (2H, t, J = 5.2 Hz), 4.01 - 4.07 (2H, m), 4.18 (2H, t, J = 4.6 Hz), 7.02 (2H, d, J = 8.8 Hz), 7.33 (2H, d, J = 8.8 Hz), 7.49 - 7.67 (8H, m).
IR (KBr) v: 2934, 2849, 1661, 1609, 1520, 1495 cm 1.
Anal. Calcd. for C35H9sN306s: C, 66.33; H, 6.84; N, 6.63.
Found C, 66.39: H, 6.76 N, 6.57.
Working Example 8 (Production of Compound 8) In THF (5m1) was dissolved 7-[4-(3-ethoxypropoxy)phenyl]-1-methanesulfonyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.20g). To the solution were added, under ice-cooling, thionyl chloride (0.06m1) and DMF (catalytic amount), and the mixture was stirred at room temperature for 2 hours. Under reduced pressure, the solvent was evaporated, and the residua was dissolved in THF (15m1). The solution was added dropwise to a solution of 4-[N-methyl-N-(tetrahydro-2H-pyran-4-yl)aminomethyl]aniline (O.llg) and triethylamine (0.19m1) in THF (5m1), under ice-cooling, and the mixture was stirred under nitrogen atmosphere at room temperature overnight. Under reduced pressure, the solvent was evaporated. To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated to give crude crystals, which were recrystallized from ethyl acetate/hexane to give 7-[4-(3-ethoxypropoxy)phenyl)-1-methanesulfonyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 8) (0.22g) as colorless crystals.
mp 157 - 160°C.
1H-NMR (8 ppm, CDC13) 1.22 (3H, t, J = 7. 0 Hz) , 1. 65 - 1. 76 (4H, m), 2.06 - 2.15 (2H, m), 2.22 (3H, s), 2.55 - 2.78 (1H, m), 2.89 (3H, s), 3.14 (2H, t, J = 5.1 Hz), 3.38 (2H, dt, J
- 2 . 6, 11. 2 Hz ) , 3 . 4 6 - 3 . 65 ( 6H, m) , 3 . 92 ( 2H, t, J = 5 . 1 Hz), 3.95 - 4.15 (4H, m), 7.00 (2H, d, J = 9.2 Hz), 7.34 (2H, d, J = 8.4 Hz), 7.49 - 7.67 (9H, m).
IR (KBr) v: 2926, 2851, 1671, 1595, 1524 cml.
Working Example 9 (Production of Compound 9) In a mixture of water: ethanol: toluene (1:1: 10, v/v, 18.0m1) were dissolved 4-(2-ethoxyethoxy)phenyl borate (315mg) and 7-bromo-1-methyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (485mg). To the solution was added potassium carbonate (332mg), and the mixture was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (46mg), and the mixture was heated to reflux under argon atmosphere for hours. The mixture was diluted with ethyl acetate, and washed with water and saturated brine, and the organic layer was dried with anhydrous magnesium sulfate.
10 The solvent was evaporated under reduced pressure, and the residue was purified with silica gel column chromatography (30g, ethyl acetate . ethanol = 9 . 1) and recrystallized from ethanol to give 7-[4-(2-ethoxyethoxy)phenyl]-1-methyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 9)(230mg, 400) as yellow crystals.
mp 122 - 125°C.
1H-NMR (200 MHz, CDC13) 8 1.26 (3H, t, J = 7.0 Hz) , 1.23 -1.76 (4H, m) , 2.20 (3H, s) , 2.53 - 2.71 (1H, m) , 2. 94 (2H, t, J - 4.4 Hz), 3.07 (3H, s), 3.32 (2H, t, J - 4.5 Hz), 3.37 (2H, td, J = 11.4, 2.9 Hz), 3.56 (2H, s), 3.62 (2H, q, J = 7.0 Hz), 3.81 (2H, t, J = 4.9 Hz), 4.01 - 4.07 (2H, m), 4.16 (2H, t, J = 5.0 Hz), 6.86 (1H, d, J = 8.6 Hz), 6.97 (2H, d, J = 8.8 Hz), 7.29 (2H, d, J = 9.0 Hz), 7.38 (1H, s), °

7.43 (1H, dd, J = 8.6, 2.2 Hz), 7.47 (2H, d, J = 8.8 Hz), 1 H (d) was concealed under 7.49, 7.54 (2H, d, J = 8.6 Hz), 7.66 (1H, s) .
IR (KBr) 2946, 2847, 1653, 1607, 1501, 1312, 1244, 1186, 1119, 814 cm 1.
Anal. Calcd. for C35H43N3~4~ C. 73.78; H, 7.61; N, 7.38.
Found C, 73.93; H, 7.39 N, 7.44.
Working Example 10 (Production of Compound 10) In DMF (5.0m1) was dissolved 1-methylsulfonyl-7-[4-(2-methylthio)ethoxyphenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (207mg). To the solution was added thionyl chloride (0.09m1), and the mixture was stirred at room temperature for 30 minutes. Under reduced pressure, the solvent was evaporated, and to the residue was added THF (10.0m1). On the other hand, to 4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]aniline dihydrochloride (168mg) was added THF (5.0m1), and then was added triethylamine (0.50m1). To the obtained mixture was added dropwise at 0°C the previously prepared acid chloride suspension, and the mixture was stirred at room temperature for 4 hours. To the mixture was added ethyl acetate, and the mixture was washed with water and saturated brine. The organic layer was dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified with silica gel column chromatography (15g, ethyl acetate ethyl acetate . ethanol . triethylamine = 100 . 10 . 1) and recrystallized from ethanol to give 1-methylsulfonyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-7-[4-(2-methylthio)ethoxyphenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 10) (176mg, 58~) as white crystals.
mp 174 - 177°C.
1H-NMR (200 MHz, CDC13) 8 1.64 - 1.77 (4H, m), 2.21 (3H, s), 2.24 (3H, s) , 2. 60 - 2.72 (1H, m) , 2.89 (3H, s) , 2. 92 (2H, t, J = 6.9 Hz), 3.14 (2H, t, J = 5.3 Hz), 3.38 (2H, td, J =
11.4, 2.9 Hz), 3.58 (2H, s), 3.92 (2H, t, J = 5.3 Hz), 4.02 - 4. 07 (2H, m) , 4.22 (2H, t, J = 6. 8 Hz) , 7 . 00 (2H, d, J =
8.8 Hz), 7.33 (2H, d, J = 8.4 Hz), 7.50 - 7.67 (9H, m).
IR (KBr) 1655, 1607, 1517, 1493, 1341, 1314, 1248, 1154cm 1.
Anal. Calcd. for C34H91N305S2: C, 64.22: H, 6.50: N, 6.61.
Found C, 64.03; H, 6.51; N, 6.55.
Working Example 11 (Production of Compound 11) In DMF (10.0m1) was dissolved 1-formyl-7-[4-(2-methylthio)ethoxyphenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (484mg). To the solution was added thionyl chloride (0.23m1), and the mixture was stirred at room temperature for 30 minutes. Under reduced pressure, the solvent was evaporated, and to the residue was added THF (10.0m1). On the other hand, to 4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]aniline dihydrochloride (444mg) was added THF (10.0m1), and then was added triethylamine (1.32m1). To the obtained mixture was added dropwise at 0°C the previously prepared acid chloride suspension, and the mixture was stirred at room temperature for 3 hours. To the mixture was added ethyl acetate and the mixture was washed with water and saturated brine. The organic layer was dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified with silica gel column chromatography (30g, ethyl acetate ethyl acetate . ethanol . triethylamine = 100 . 10 . 1) and recrystallized from ethanol to give 1-formyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-7-[4-(2-methylthio)ethoxyphenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 11) (555mg, 750) as white crystals.
mp 180 - 183°C.
1H-NMR (200 MHz, CDC13) 8 1.64 - 1.77 (4H, m), 2.21 (3H, s), 2.24 (3H, s), 2.59 - 2.67 (1H, m), 2.92 (2H, t, J = 6.8 Hz), 3.04 (2H, t, J = 4.6 Hz), 3.37 (2H, td, J = 11.2, 2.9 Hz), 3.57 (2H, s), 3.92 (2H, t, J = 5.3 Hz), 4.01 - 4.07 (2H, m), 4.22 (2H, t, J = 6.8 Hz), 7.01 (2H, d, J = 8.8 Hz), 7.20 (1H, d, J = 8.0 Hz), 7.32 (2H, d, J = 8.8 Hz), 7.47 - 7.58 (7H, m), 7.68 (1H, d, J = 1.8 Hz), 8.55 (1H, s) .

IR (KBr) 1667, 1607, 1514, 1497, 1360, 1314, 1246, 824 cm 1.
Anal. Calcd. for C3qH39N3O9S (0.2H20 additive) : C, 69.29; H, 6.74 N, 7.13. Found C, 69.09; H, 6.58: N, 7.01.
Working Example 12 (Production of Compound 12) In a mixture of water . ethanol . toluene (1 . 1 .
10, v/v, 18.0m1) were dissolved 4-(2-propoxyethoxy)phenyl borate (242mg) and 7-bromo-1-methyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxarnide (436mg). To the solution was added potassium carbonate (299mg), and the mixture was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (42mg), and the mixture was heated to reflux under argon atmosphere for 10 hours. The mixture was diluted with ethyl acetate, and washed with water and saturated brine, and the organic layer was dried with anhydrous magnesium sulfate.
The solvent was evaporated under reduced pressure, and the residue was purified with silica gel column chromatography (30g, ethyl acetate . ethanol .
triethylalnine = 180 . 20 . 1) and recrystallized from ethanol/hexane to give 1-methyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-7-[4-(2-propoxyethoxy)phenyl]-2,3-dihydro- 1H-1-benzazepine-4-carboxamide (Compound 12) (186mg, 35$) as yellow crystals.

mp 136 - 138C.

1H-NMR (200 MHz, CDC13) 8 0.94 (3H, t, J = 7.3 Hz), 1.65 (2H, sextet, J - 7.2 Hz), 1.69 - 1.76 (4H, m), 2.21 (3H, s), 2.57 - 2.72 (1H, m), 2.96 (2H, t, J = 4.4 Hz), 3.09 (3H, s), 3.32 - 3.43 (4H, m), 3.51 (2H, t, J = 6.8 Hz), 3.56 (2H, s), 3.81 (2H, t, J = 5.0 Hz), 4.01 - 4.06 (2H, m), 4.16 (2H, t, J = 4. 9 Hz) , 6. 88 (1H, d, J = 8.4 Hz) , 6. 98 (2H, J 8.
d, = 8 Hz), 7.30 (2H, d, J = 8.6 Hz), 7.40 - 7.56 (8H, m).

IR (KBr) 1651, 1607, 1514, 150 1, 1312, 1244, 1186 ml.
c Anal. Calcd. for C36H95N3Oq (0. 3H20 additive) : C, H, 73.39;

7.80: N, 7.13. Found C, 73.12 H, 7.67 N, 7.08.

Working Example 13 (Production of Compound 13) In a mixture of water . ethanol . toluene (1 . 1 .
10, v/v, l8.Oml) were dissolved 4-(3-ethoxypropoxy)phenyl borate (250mg) and 7-bromo-1-methyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (450mg). To the solution was added potassium carbonate (308mg), and the mixture was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (43mg), and the mixture was refluxed under argon atmosphere for 10 hours.
The mixture was diluted with ethyl acetate, and washed with water and saturated brine, and the organic layer was dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified with silica gel column chromatography (25g, ethyl acetate . ethanol . triethylamine = 100 . 10 . 1) and recrystallized from ethanol/hexane to give 7-[4-(3-ethoxypropoxy)phenyl]-1-methyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 13) (359mg, 66%) as yellow crystals.
mp 98 - 100°C.
1H-NMR (200 MHz, CDC13) 8 1.21 (3H, t, J = 6. 9 Hz) , 1. 63 -1.79 (4H, m), 2.07 (2H, quint, J = 6.3 Hz), 2.21 (3H, s), 2.54 - 2.75 (1H, m), 2.96 (2H, t, J = 4.4 Hz), 3.09 (3H, s), 3.31 - 3.43 (4H, m), 3.51 (2H, q, J = 7.0 Hz), 3.56 (2H, s), 3.62 (2H, t, J = 6.3 Hz), 4.00 - 4.07 (2H, m), 4.10 (2H, t, J = 6.2 Hz), 6.88 (1H, d, J = 8.6 Hz), 6.97 (2H, d, J = 8.8 Hz), 7.30 (2H, d, J - 8.6 Hz), 7.40 - 7.56 (3H, m), 7.40 (1H, s), 7.48 (2H, d, J = 9.0 Hz), 7.54 (2H, d, J = 8.6 Hz).
IR (KBr) 1647; 1607, 1514, 1501, 1312, 1244, 1182, 1115cm 1.
Anal. Calcd. for C36H95N3O9 (0.2H20 additive) : C, 73.62; H, 7.79; N, 7.15. Found C, 73.53: H, 7.63 N, 7.11.
Working Example 14 (Production of Compound 14) In DMF (9.5m1) was dissolved 1-formyl-7-[4-(2-propoxy)ethoxyphenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (379mg). To the solution was added thionyl chloride (0.18m1), and the mixture was stirred at room temperature for 30 minutes. Under reduced pressure, the solvent was evaporated, and to the residue was added THF (15.0m1). On the other hand, to 4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]aniline dihydrochloride (337mg) was added THF (lO.Oml), and then was added triethylamine (1.00m1). To the obtained mixture was added dropwise at 0°C the previously prepared acid chloride suspension, and the mixture was stirred at room temperature for 15 hours. To the mixture was added ethyl acetate, and the mixture was washed with water and saturated brine. The organic layer was dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified with silica gel column chromatography (35g, ethyl acetate ethyl acetate . ethanol = 10 . 1 ~ ethyl acetate .
ethanol . triethylamine = 100 . 10 . 1) and recrystallized from ethanol to give 1-formyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-7-[4-(2-propoxy)ethoxyphenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxarnide (Compound 14) (459mg, 800) as white crystals.
mp 187 - 189°C.
1H-NMR (200 MHz, CDC13) 8 0. 95 (3H, t, J = 7. 4 Hz) , 1.57 -1.74 (6H, m) , 2.20 (3H, s) , 2. 56 - 2.72 (1H, m) , 3.03 (2H, t, J = 5.2 Hz) , 3. 37 (2H, td, J = 11 . 0, 2. 8 Hz) , 3. 52 (2H, t, J - 6.8 Hz), 3.57 (2H, s), 3.82 (2H, t, J - 4.9 Hz), 3.92 (2H, t, J = 5.3 Hz), 4.01 - 4.07 (2H, m), 4.18 (2H, t, J = 4.9 Hz), 7.03 (2H, d, J = 8.8 Hz), 7.19 (1H, d, J = 8.4 Hz), 7.31 (2H, d, J - 8.4 Hz), 7.46 - 7.58 (7H, m), 7.67 ( 1H, s ) , 8 . 55 ( 1H, s ) .
IR (KBr) 1667, 1609, 1518, 1497, 1360, 1314, 1248, 824 cm 1.
Anal. Calcd. for C36H43N3O5: C, 72.34; H, 7.25 N, 7.03.
Found C, 72.39 H, 7.32: N, 7.08.
Working Example 15 (Production of Compound 15) In DMF (6.5m1) was dissolved 1-methylsulfonyl-7-[4-(2-propoxy)ethoxyphenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (296mg). To the solution was added thionyl chloride (0.12m1), and the mixture was stirred at room temperature for 30 minutes. Under reduced pressure, the solvent was evaporated, and to the residue was added THF (15.0m1). On the other hand, to 4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]aniline dihydrochloride (234mg) was added THF (10.0m1), and then was added triethylamine (0.69m1). To the obtained mixture was added dropwise at 0°C the previously prepared acid chloride suspension, and the mixture was stirred at room temperature for 3 hour. To the mixture was added ethyl acetate, and the mixture was washed with water and saturated brine. The organic layer was dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified with silica gel column chromatography (25g, ethyl acetate ethyl acetate . ethanol . triethylamine = 100 . 10 . 1) and recrystallized from ethanol to give 1-methylsulfonyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-7-[4-(2-propoxy)ethoxyphenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 15) (248mg. 58~) as white crystals.
mp 161 - 162°C.
1H-NMR (200 MHz, CDC13) 8 0.95 (3H, t, J = 7.3 Hz), 1.65 (2H, sextet, J - 7.1 Hz), 1.69 - 1.77 (4H, m), 2.21 (3H, s), 2.54 - 2.70 (1H, m), 2.88 (3H, s), 3.13 (2H, t, J = 5.0 Hz), 3. 37 (2H, td, J = 11. 4, 5. 6 Hz) , 3. 52 (2H, t, J = 6. 8 Hz) , 3.57 (2H, s), 3.82 (2H, t, J - 4.8 Hz), 3.91 (2H, t, J -5.7 Hz), 4.01 - 4.07 (2H, m), 4.18 (2H, t, J - 5.0 Hz), 7.00 - 7.04 (2H, m), 7.32 (2H, d, J = 8.4 Hz), 7.50 (2H, d, J = 8.8 Hz), 7.48 - 7.66 (7H, m).
IR (KBr) 1663, 1609, 1516, 1493, 1343, 1310, 1248, 1154, 667 cm 1.
Anal. Calcd. for C36H9sNsOsS: C, 66.74; H, 7.00 N, 6.49.
Found C, 66.56; H, 7.03: N, 6.36.
Working Example 16 (Production of Compound 16) In a mixture of water . ethanol . toluene (1 . 1 .
10, v/v, l8.Oml) were dissolved 4-(2-ethoxyethoxy)phenyl borate (339mg) and 7-bromo-1-ethyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (537mg). To the solution was added potassium carbonate (357mg), and the mixture was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (50mg), and the mixture was heated to reflux under argon atmosphere for 14 hours. The mixture was diluted with ethyl acetate, and washed with water and saturated brine, and the organic layer was dried with anhydrous magnesium sulfate.
The solvent was evaporated under reduced pressure, and the residue was purified with silica gel column chromatography (35g, ethyl acetate ~ ethyl acetate .
ethanol = 10 . 1 -~ ethyl acetate . ethanol .
triethylamine = 100 . 10 . 0.5) and recrystallized from ethyl acetate/IPE to give 7-[4-(2-ethoxyethoxy)phenyl]-1-ethyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 16) (332mg, 53~) as yellow crystals.
mp 114.5 - 116.5°C.
1H-NMR (200 MHz, CDC13) b 1.26 (3H, t, J = 6.9 Hz), 1.32 (3H, t, J = 7.1 Hz), 1.63 - 1.76 (4H, m), 2.21 (3H, s), 2.59 -2.69 (1H, m), 2.91 (2H, t, J = 4.8 Hz), 3.31 - 3.42 (4H, m), 3.44 (2H, q, J - 7.0 Hz), 3.57 (2H, s), 3.64 (2H, t, J -6.9 Hz), 3.82 (2H, t, J - 4.8 Hz), 4.01 - 4.06 (2H, m), 4.16 (2H, t, J = 5.0 Hz), 6.91 (1H, d, J = 8.8 Hz), 6.98 (2H, d, J = 9.2 Hz), 7.30 (2H, d, J = 8.4 Hz), 7.40 (1H, s), 7.47 (2H, d, J = 9.2 Hz) , 7. 53 (2H, d, J = 8. 4 Hz) , 7. 40 -7.56 (3H, m).
IR (KBr) 1651, 1607, 1514, 1501, 1312, 1244, 1175, 1140, 1119 cm 1.
Anal. Calcd. for C36H45N3~9 (0.2H20 additive) : C, 73.62: H, 7.79; N, 7.15. Found C, 73.45: H, 7.85; N, 7.05.
Working Example 17 (Production of Compound 17) In a mixture of water . ethanol . toluene (1 . 1: 10, v/v, 18.0m1) were dissolved 4-(2-propoxyethoxy)phenyl borate (272mg) and 7-bromo-1-ethyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (404mg). To the solution was added potassium carbonate (269mg), and the mixture was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (37mg), and the mixture was heated to reflux under argon atmosphere for 14 hours. The mixture was diluted with ethyl acetate, and washed with water and saturated brine, and the organic layer was dried with anhydrous magnesium sulfate.
The solvent was evaporated under reduced pressure, and the residue was purified with silica gel column chromatography (30g, ethyl acetate -~ ethyl acetate .

ethanol = 10:1 -> ethyl acetate . ethanol . triethylamine - 100 . 10 . 0.5) and recrystallized from ethyl acetate/IPE to give 1-ethyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-7-[4-(2-propoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 17) (221mg, 46~) as yellow crystals.
mp 106 - 108°C.
1H-NMR (200 MHz, CDC13) b 0.94 (3H, t, J = 7.5 Hz) , 1.32 (3H, t, J = 6. 9 Hz) , 1. 65 (2H, sextet, J = 7. 1 Hz) , 1..70 - 1.76 ( 4H, m) , 2 . 21 ( 3H, s ) , 2 . 56 - 2 . 69 ( 1H, m) , 2 . 92 ( 2H, t, J
- 4 . 0 Hz) , 3. 31 - 3. 46 (6H, m) , 3. 51 (2H, t, J = 6. 8 Hz) , 3.56 (2H, s), 3.81 (2H, t, J = 4.9 Hz), 4.01 - 4.06 (2H, m), 4.16 (2H, t, J = 5.0 Hz), 6.92 (1H, d, J = 8.4 Hz), 6.98 (2H, d, J = 8.8 Hz), 7.30 (2H, d, J = 8.8 Hz), 7.40 (1H, s), 7.47 (2H, d, J = 8.8 Hz) , 7.54 (2H, d, J = 8.8 Hz) , 7.40 -7 . 56 ( 3H, m) .
IR (KBr) 2928, 1651, 1645, 1607, 1514, 1501, 1314, 1244, 1175 cm 1.
Anal. Calcd. for C37H9~N309 (0.3H20 additive) : C, 73.67; H, 7.95: N, 6.97. Found C, 73.52 H, 7.76: N, 6.95.
Working Example 18 (Production of Compound 18) In a mixture of water . ethanol . toluene (1 . 1 .
10, v/v, 18.0m1) were dissolved 4-(2-butoxyethoxy)phenyl borate (324mg) and 7-bromo-1-methyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide ( 440mg). To the solution was added potassium carbonate (301mg), and the mixture was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (42mg), and the mixture was refluxed under argon atmosphere for 10 hours.
The mixture was diluted with ethyl acetate, and washed with water and saturated brine, and the organic layer was dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified with silica gel column chromatography (30g, ethyl acetate --~ ethyl acetate . ethanol = 10 . 1 -~ ethyl acetate . ethanol . triethylamine = 100 . 10 . 0.5) and recrystallized from ethyl acetate/IPE to give 7-[4-(2-butoxYethoxy)phenyl]-1-methyl-N-[4-[ [N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 18) (287mg, 530) as yellow crystals.
mp 107 - 110°C.
1H-NMR (200 MHz, CDC13) 8 0.93 (3H, t, J = 7.2 Hz), 1.39 (2H, sextet, J - 7.3 Hz), 1.55 - 1.79 (6H, m), 2.21 (3H, s), 2.57 - 2.75 (1H, m), 2.96 (2H, t, J = 4.4 Hz), 3.09 (3H, s), 3.31 - 3.38 (2H, m) , 3. 37 (2H, td, J = 11. 6, 2.7 Hz) , 3. 55 (2H, t, J = 6.6 Hz), 3.57 (2H, s), 3.81 (2H, t, J = 5.0 Hz), 4.00 - 4.08 (2H, m), 4.16 (2H, t, J = 4.9 Hz), 6.88 (1H, d, J = 8.6 Hz), 6.96 - 7.01 (2H, m), 7.30 (2H, d, J = 8.4 Hz), 7.40 - 7.56 (4H, m), 7.48 (2H, d, J = 9.0 Hz), 7.54 (2H, d, J = 8.6 Hz) .
IR (KBr) 2955, 2936, 1651, 1607, 1514, 1312, 1244, 1186cm 1.
Anal. Calcd. for C3~HQ~N309 (O.lHzO additive) : C, 74.12; H, 7.93; N, 7.01. Found C, 73.90 H, 7.82 N, 7.12.
Working Example 19 (Production of Compound 19) In a mixture of water . ethanol . toluene (1 . 1 .
10, v/v, 18.0m1) were dissolved 4-(2-butoxyethoxy)phenyl borate (301mg) and 7-bromo-1-ethyl-N-[ 4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (420mg). To the solution was added potassium carbonate (279mg), and the mixture was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (39mg), and the mixture was refluxed under argon atmosphere for 14 hours.
The mixture was diluted with ethyl acetate, and washed with water and saturated brine, and the organic layer was dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified with silica gel column chromatography (30g, ethyl acetate -~ ethyl acetate . ethanol = 10 . 1 ~ ethyl acetate . ethanol . triethylamine = 100 . 10 . 0.5) and recrystallized from ethyl acetate/IPE to give 7-[4-(2-butoxyethoxy)phenyl]-1-ethyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-H-1-benzazepine-4-carboxamide (Compound 19) (218mg, 420) as yellow crystals.
mp 102 - 106°C.
1H-NMR (200 MHz, CDC13) 8 0.93 (3H, t, J = 7.1 Hz), 1.32 (3H, t, J = 7.0 Hz) , 1.39 (2H, sextet, J = 7.4 Hz) , 1.54 - 1.76 (6H, m), 2.21 (3H, s), 2.54 - 2.72 (1H, m), 2.92 (2H, t, J
- 4.6 Hz), 3.31 - 3.50 (6H, m), 3.55 (2H, t, J = 6.6 Hz), 3.57 (2H, s), 3.81 (2H, t, J = 4.9 Hz), 4.01 - 4.07 (2H, m), 4.16 (2H, t, J = 5.0 Hz), 6.92 (1H, d, J = 8.6 Hz), 6.98 (2H, d, J = 8. 8 Hz) , 7. 30 (2H, d, J = 8 . 4 Hz) , 7 . 40 (1H, s) , 7.44 - 7.56 (3H, m), 7.47 (2H, d, J = 9.0 Hz), 7.54 (2H, d, J = 8.4 Hz).
IR (KBr) 2953, 2932, 1651, 1605, 1514, 1501, 1406, 1314, 1244, 1175 cm 1.
Anal. Calcd. for C38HQ9N3O9 (0.2H20 additive) : C, 74.16; H, 8.09 N, 6.83. Found C, 73.92 H, 8.19: N, 6.59.
Working Example 20 (Production of Compound 20) In a mixture of water . ethanol . toluene (1 . 1 .
10, v/v. 18.0m1) were dissolved 4-[(2-ethoxy)ethoxy]-3-fluorophenyl borate (355mg) and 7-bromo-1-formyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (517mg). To the solution was added potassium carbonate (344mg), and the mixture was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (48mg), and the mixture was heated to reflux under argon atmosphere for 10 hours. The mixture was diluted with ethyl acetate, and washed with water and saturated brine, and the organic layer was dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified with silica gel column chromatography (30g, ethyl acetate ~ ethyl acetate . ethanol = 10 . 1 ~ ethyl acetate . ethanol .
triethylamine = 100 . 10 :1) and recrystallized from ethanol to give 7-[ 4-(2-ethoxy)ethoxy-3-fluorophenyl]-1-formyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 20) (476mg, 76%) as white crystals.
mp 188 - 191°C.
1H-NMR (200 MHz, CDC13) b 1.26 (3H, t, J = 7. 1 Hz) , 1. 64 -1.77 (4H, m) , 2.20 (3H, s) , 2.57 - 2.72 (1H, m) , 3.04 (2H, t, J = 5.2 Hz), 3.37 (2H, td, J = 11.3, 2.9 Hz), 3.57 (2H, s), 3.63 (2H, q, J - 7.0 Hz), 3.85 (2H, t, J - 4.9 Hz), 3.92 (2H, t, J = 5.6 Hz), 4.01 - 4.07 (2H, m), 4.25 (2H, t, J = 4.9 Hz), 7.09 (1H, t, J = 8.6 Hz), 7.20 (1H, d, J = 8.2 Hz), 7.29 - 7.36 (2H, m), 7.32 (2H, d, J - 8.0 Hz), 7.45 (1H, s), 7.53 (2 H + 1H, d, J = 8.8 Hz), 7.56 (1H, s), 7.65 (1H, d, J = 2.2 Hz), 8.55 (1H, s).
IR (KBr) 1669, 1501, 1358, 1314, 1269, 1238, 1198, 1138, 1125 cm 1.
Anal. Calcd. for C35H9oFN309: C, 69.86: H, 6.70 N, 6.98.
Found C, 69.66 H, 6.40: N, 6.71.
Working Example 21 (Production of Compound 21) In a mixture of water . ethanol . toluene (1 . 1 .
10, v/v, 18.0m1) were dissolved 3-chloro-4-(2-ethoxy)ethoxyphenyl borate (280mg) and 7-bromo-1-formyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (380mg). To the solution was added potassium carbonate (253mg), and the mixture was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrkistriphenylphosphinepalladium (35mg), and the mixture was heated to reflux under argon atmosphere for 10 hours. The mixture was diluted with ethyl acetate, and washed with water and saturated brine, and the organic layer was dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified with silica gel column chromatography (25g, ethyl acetate ~ ethyl acetate . ethanol = 10 . 1 ~ ethyl acetate . ethanol .
triethylarnine = 100 . 10 . 0.5) and recrystallized from ethanol to give 7-[3-chloro-4-(2-ethoxy)ethoxyphenyl]-1-formyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 21) (342mg, 73%) as white crystals.
mp 198 - 200°C.
1H-NMR (200 MHz, CDC13) 8 1.26 (3H, t, J = 6. 9 Hz) , 1. 64 -1.76 (4H, m) , 2.20 (3H, s) , 2.57 - 2. 69 (1H, m) , 3.04 (2H, t, J = 5 . 2 Hz ) , 3 . 37 ( 2H, td, J = 11. 1, 2 . 9 Hz ) , 3 . 57 ( 2H, s), 3.67 (2H, q, J - 7.0 Hz), 3.88 (2H, t, J - 5.0 Hz), 3.91 (2H, t, J = 6.O Hz), 4.01 - 4.06 (2H, m), 4.24 (2H, t, J = 4.9 Hz), 7.05 (1H, d, J = 8.4 Hz), 7.20 (1H, d, J = 8.2 Hz), 7.32 (2H, d, J = 8.4 Hz), 7.43 (1H, dd, J = 8.6, 2.4 Hz), 7.44 (1H, s), 7.54 (2 H + 1H, d, J = 8.4 Hz), 7.56 (1H, s), 7.61 (1H, d, J - 2.2 Hz), 7.65 (1H, d, J - 2.2 Hz), 8.55 (1H, s).
IR (KBr) 1669, 1599, 1516, 1493, 1360, 1314, 1292, 1260, 1140, 1065 cm 1.
Anal. Calcd. for C35H9oC1N3O5: C, 68.00: H, 6.52 N, 6.80.
Found C, 67.71; H, 6.43; N, 6.71.
Working Example 22 (Production of Compound 22) In a mixture of water . ethanol . toluene (1 . 1 .
10, v/v, 18.0m1) were dissolved 4-(3-propoxy)propoxyphenyl borate (270mg) and 7-bromo-1-formyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (377mg). To the solution was added potassium carbonate (251mg), and the mixture was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (35mg), and the mixture was heated to reflux under argon atmosphere for 10 hours. The mixture was diluted with ethyl acetate, and washed with water and saturated brine, and the organic layer was dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified with silica gel column chromatography (25g, ethyl acetate ~ ethyl acetate . ethanol = 10 . 1 -~ ethyl acetate . ethanol .
triethylamine = 100 . 10 . 0.5) and recrystallized from ethanol to give 1-formyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-7-[4-(3-propoxy)propoxyphenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 22) (304mg, 66~) as white crystals.
mp 174 - 177°C.
1H-NMR (200 MHz, CDC13) 8 0. 92 (3H, t, J = 7.3 Hz) , 1. 60 (2H, sextet, J = 7.1 Hz), 1.69 - 1.76 (4H, m), 2.08 (2H, quint, J = 6.2 Hz), 2.20 (3H, s), 2.59 - 2.69 (1H, m), 3.03 (2H, t, J = 4.9 Hz), 3.31 - 3.41 (2H, m), 3.41 (2H, t, J = 6.6 Hz), 3.57 (2H, s), 3.61 (2H, t, J = 6.0 Hz), 3.92 (2H, t, J -5.3 Hz), 4.01 - 4.09 (2H, m), 4.12 (2H, t, J - 6.4 Hz), 7.00 (2H, d, J = 8.8 Hz), 7.19 (1H, d, J = 8.0 Hz), 7.31 (2H, d, J = 8.4 Hz), 7.46 (1H, s), 7.51 (2H, d, J = 8.4 Hz), 7.54 (2H, d, J = 8.4 Hz), 7.49 - 7.58 (2H, m), 7.67 (1H, d, J = 1.8 Hz), 8.54 (1H, s).
IR (KBr) 2940, 1669, 1607, 1516, 1497, 1360, 1314, 1248, 1119 cm 1.
Anal. Calcd. for C3,H45N305: C, 72.64; H, 7.41; N, 6.87.
Found C, 72.46; H, 7.62; N, 6.95.
Working Example 23 (Production of Compound 23) In a mixture of water . ethanol . toluene (1 . 1 .
10, v/v, 18.0m1) were dissolved 3-ethoxy-4-(2-propoxy)ethoxyphenyl borate (324mg) and 7-bromo-1-formyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (401mg). To the solution was added potassium carbonate (267mg), and the mixture was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (37mg), and the mixture was heated to reflux under argon atmosphere for 10 hours. The mixture was diluted with ethyl acetate, and washed with water and saturated brine, and the organic layer was dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified with silica gel column chromatography (25g, ethyl acetate -~ ethyl acetate . ethanol = 10 . 1 ~ ethyl acetate . ethanol .
triethylamine = 100 . 10 :0.5) and recrystallized from ethyl acetate/IPE to give 7-[3-ethoxy-4-(2-propoxy)ethoxyphenyl]-1-formyl-N-[4-[(N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 23) ( 317mg, 615 ) as white crystals .
mp 117 - 119°C .
1H-NMR ( 200 MHz, CDC13) b 0 . 94 ( 3H, t, J = 7 . 3 Hz ) , 1. 48 ( 3H, t, J = 6.9 Hz), 1.64 (2H, sextet, J = 7.2 Hz), 1.64 - 1.76 (4H, m) , 2.20 (3H, s) , 2.57 - 2.70 (1H, m) , 3.03 (2H, t, J
- 3 . 6 Hz ) , 3 . 37 ( 2H, td, J = 11. 2, 2 . 7 Hz ) , 3 . 53 ( 2H, t, J
- 6.7 Hz), 3.56 (2H, s), 3.84 (2H, t, J = 5.1 Hz), 3.92 (2H, t, J = 5. 3 Hz) , 4. O1 - 4. 07 (2H, m) , 4 . 16 (2H, q, J = 7. 1 Hz), 4.22 (2H, t, J = 5.2 Hz), 7.03 (1H, d, J = 8.8 Hz), 7.10 (1H, s) , 7.11 (1H, dd, J = 8.4, 2.2 Hz) , 7.18 (1H, d, J = 8.4 Hz), 7.32 (2H, d, J = 8.4 Hz), 7.50 (2H, d, J = 8.4 Hz), 7.54 (1H, d, J = 8.4 Hz), 7.57 (1H, d, J = 2.6 Hz), 7 . 60 ( 1H, s ) , 7 . 57 ( 1H, d, J = 1. 8 Hz ) , 8 . 54 ( 1H, s ) .
IR (KBr) 2942, 1671, 1597, 1514, 1499, 1408, 1360, 1316, 1254, 1202, 1140 cm 1.
Anal. Calcd. for C38HQ,N3O6 (0.1H20 additive) : C, 70.92; H, 7.39; N, 6.53. Found C, 70.71; H, 7.36; N, 6.47.
Working Example 24 (Production of Compound 24) In a mixture of water . ethanol . toluene (1 . 1 .
10, v/v, 18.0m1) were dissolved (2,3-dihydro-1,4-benzodioxin-6-yl) borate (221mg) and 7-bromo-1-methyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (397mg). To the solution was added potassium carbonate (272mg), and the mixture was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (38mg), and the mixture was heated to reflux under argon atmosphere for 10 hours. The mixture was diluted with ethyl acetate, and washed with water and saturated brine, and the organic layer was dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified with silica gel column chromatography (35g, ethyl acetate . ethanol =
. 1) and recrystallized from ethanol to give 7-(2,3-15 dihydro-1,4-benzodioxin-6-yl)-1-methyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 24) (215mg, 490) as yellow crystals.
mp 164 - 165°C .
20 1H-NMR (200 MHz, CDC13) b 1.63 - 1.76 (4H, m), 2.20 (3H, s), 2.53 - 2.73 (1H, m), 2.95 (2H, t, J = 4.4 Hz), 3.07 (3H, s), 3.31 - 3.43 (4H, m), 3.56 (2H, s), 4.01 - 4.07 (2H, m), 4.29 (4H, s), 6.86 (1H, d, J = 8.4 Hz), 6.90 (1H, d, J =
9.6 Hz), 7.05 (1H, dd, J - 10.4, 2.2 Hz), 7.07 (1H, s), 7.29 (2H, d, J = 8.6 Hz), 7.37 - 7.55 (3H, m), 7.54 (2H, d, J = 8.6 Hz), 7.62 (1H, s).
IR (KBr) 2948, 1644, 1597, 1514, 1497, 1406, 1312, 1283, 1246, 1188, 1071, 810, 733 cml.
Anal. Calcd. for C33H3~N3O9 (0.2H20 additive) : C, 72.96; H, 6.94; N, 7.73. Found C, 72.86; H, 6.91 N, 7.70.
Working Example 25 (Production of Compound 25) In a mixture of water . ethanol . toluene (1 . 1 .
10. v/v, 18.0m1) were dissolved 4-(2-ethoxyethoxy)phenyl borate (246mg) and 7-bromo-1-propyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (400mg). To the solution was added potassium carbonate (259mg), and the mixture was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (36mg), and the mixture was heated to reflux under argon atmosphere for 10 hours. The mixture was diluted with ethyl acetate, and washed with water and saturated brine, and the organic layer was dried with anhydrous magnesium sulfate.
The solvent was evaporated under reduced pressure, and the residue was purified with silica gel column chromatography (30g, ethyl acetate ~ ethyl acetate .
ethanol = 10 . 1) and recrystallized from ethyl acetate-IPE to give 7-[4-(2-ethoxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-1-propyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 25) (216mg, 46%) as yellow crystals.
mp 144 - 147°C.
1H-NMR (200 MHz, CDC13) 8 0.99 (3H, t, J = 7.4 Hz), 1.26 (3H, t, J = 6.9 Hz), 1.63 - 1.84 (6H, m), 2.20 (3H, s), 2.56 -2.69 (1H,m), 2.91 (2H, t, J = 4.4 Hz), 3.28 - 3.43 (6H, m), 3.56 (2H,s), 3.62 (2H, q, J = 7.0 Hz), 3.81 (2H, t, J -4.9 Hz), 4.01 - 4.06 (2H, m), 4.16 (2H, t, J - 4.8 Hz), 6.90 (1H,d, J = 8.6 Hz), 6.98 (2H, d, J = 8.8 Hz), 7.29 (2H, d, = 8.4 Hz), 7.37 7.55 (8H, m).
J -IR (KBr) 2957, 2940, 1644, 1605, 1499, 1406, 1312, 1240, 1177, 1140, cm 1.

Anal. Calcd. for C3,Hq~N3Oq: C, 74.34; H, 7.92; N, 7.02.
Found C, 74.13: H, 7.76 N, 7.17.
Working Example 26 (Production of Compound 26) In a mixture of water . ethanol . toluene (1 . 1 .
10, v/v, 18.0m1) were dissolved 4-(2-propoxyethoxy)phenyl borate (260mg) and 7-bromo-1-propyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (396mg). To the solution was added potassium carbonate (256mg), and the mixture was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (36mg), and the mixture was heated to reflux under argon atmosphere for hours. The mixture was diluted with ethyl acetate, and washed with water and saturated brine, and the organic layer was dried with anhydrous magnesium sulfate.
The solvent was evaporated under reduced pressure, and 5 the residue was purified with silica gel column chromatography (25g, ethyl acetate --~ ethyl acetate ethanol = 10 . 1) and recrystallized from ethyl acetate-IPE to give N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-7-[4-(2-propoxyethoxy)phenyl]-1-10 propyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 26) (252mg, 53g) as yellow crystals.
mp 128 - 130°C.
1H-NMR (200 MHz, CDC13) 8 0.94 (3H, t, J = 7.5 Hz), 0.99 (3H, t, J = 7. 6 Hz) , 1.59 - 1.81 (8H, m) , 2.20 (3H, s) , 2.56 2. 69 (1H, m) , 2. 92 (2H, t-like) , 3.28 - 3.43 (6H, m) , 3. 51 (2H, t, J = 6.7 Hz), 3.56 (2H, s), 3.81 (2H, t, J = 5.0 Hz), 4.01 - 4.06 (2H, m), 4.16 (2H, t, J = 5.0 Hz), 6.90 (1H, d, J = 8.4 Hz), 6.98 (2H, d, J = 8.4 Hz), 7.29 (2H, d, J = 8.8 Hz), 7.38 - 7.55 (8H, m).
IR (KBr) 2957, 2940, 1644, 1605, 1499, 1406, 1312, 1240, 1177, 1140, 1121 cml.
Anal. Calcd. for C38H49N3O4: C, 74.60; H, 8.07; N, 6.87.
Found C, 74.31: H, 8.21; N, 7.12.
Working Example 27 (Production of Compound 27) In a mixture of water . ethanol . toluene (1 . 1 .

10, v/v, 24.0m1) were dissolved 4-(2-butoxyethoxy)phenyl borate (519mg) and 7-bromo-1-propyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (745mg). To the solution was added potassium carbonate (482mg), and the mixture was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (67mg), and the mixture was refluxed under argon atmosphere for 10 hours.
The mixture was diluted with ethyl acetate, and washed with water and saturated brine, and the organic layer was dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified with silica gel column chromatography (35g, ethyl acetate ~ ethyl acetate . ethanol = 10 . 1) and recrystallized from ethyl acetate-IPE to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-1- propyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 27) (453mg, 500) as yellow crystals.
mp 122 - 124°C.
1H-NMR (200 MHz, CDC13) 8 0.93 (3H, t, J = 7.1 Hz), 0.99 (3H, t, J = 7.3 Hz), 1.39 (2H, sextet, J = 7.2 Hz), 1.54 - 1.80 ( 8H, m) , 2 . 20 ( 3H, s ) , 2 . 53 - 2 . 71 ( 1H, m) , 2 . 91 ( 2H, t, J
- 4.0 Hz), 3.27 - 3.43 (6H, m), 3.52 - 3.58 (4H, m), 3.80 (2H, t, J = 5. 0 Hz) , 4. O1 - 4. 06 (2H, m) , 4. 15 (2H, t, J =
4.7 Hz) , 6. 89 (1H, d, J = 8. 8 Hz) , 6. 97 (2H, d, J = 8.8 Hz) , 7.29 (2H, d, J = 8.4 Hz), 7.37 - 7.59 (8H, m).
IR (KBr) 2957, 2940, 1644, 1605, 1499, 1406, 1312, 1240, 1177, 1140, 1121 cm 1.
Anal. Calcd. for C39HS1N3O9: C, 74.85: H, 8.21; N, 6.71.
Found C, 74.64; H, 8.36 N, 6.93.
Working Examples 28 (Production of Compound 28) In 1N hydrochloric acid (50m1) and THF (50m1) was dissolved 7-[4-(2-butoxyethoxy)phenyl]-1-formyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (1.4g). The solution was refluxed for 4.5 hours, concentrated, neutralized with 1N sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 28) (1.0g) as yellow crystals.
mp 119 - 123°C.
1H-NMR (8 ppm, CDC13) 0. 93 (3H, t, J = 7.3 Hz) , 1.34 - 1.75 (8H, m), 2.21 (3H, s), 2.60 - 2.65 (1H, m), 2.96 (2H, t like) , 3. 32 - 3. 58 (8H, m) , 3. 80 (2H, t, J = 5. 0 Hz) , 4. O1 4.07 (2H, m), 4.16 (2H, t, J = 5.0 Hz), 4.57 (1H, br), 6.70 (1H, d, J = 8.2 Hz) , 6. 98 (2H, d, J = 9.0 Hz) , 7.26 -7.32 (4H, m), 7.43 - 7.56 (5H, m).
IR (KBr) v: 3328, 2946, 2851, 1651, 1609, 1514, 1499 cml.
Anal. Calcd. for C36H4sN309 ' 0.25H20: C, 73. 50; H, 7.80; N, 7.14. Found C, 73.54 H, 7.79 N, 7.15.
Working Example 29 (Production of Compound 29) In DMF (5m1) was dissolved 1-propionyl-7-[4-(2-propoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.2g). Under ice-cooling, to the solution was added thionyl chloride (0.09m1). The mixture was stirred at room temperature for 30 minutes.
The solvent was evaporated under reduced pressure. In THF (15m1) was dissolved the residue, which was added dropwise to a solution of 4-[N-methyl-N-(tetrahydro-2H-pyran-4-yl)aminomethyl]aniline (0.15g) and triethylamine (0.34m1) in THF (5m1), under ice-cooling. The mixture was stirred at room temperature overnight under nitrogen atmosphere. The solvent was evaporated under reduced solvent. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated to give crude crystals, which were recrystallized from ethyl acetate-hexane to give 1-propionyl-7-[4-(2-propoxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine -4-carboxamide (Compound 29) (0.1g) as pale yellow crystals.
mp 167 - 169°C.
1H-NMR (b ppm, CDC13) 0 . 95 ( 3H, t, J = 7 . 3 Hz ) , 1. 08 ( 3H, t, J = 7.5 Hz), 1.58 - 1.75 (6H, m), 2.12 - 2.21 (1H, m), 2.21 (3H, s) , 2. 40 - 2. 75 (2H, m) , 2.75 - 3. 00 (2H, m) , 3. 10 -3.30 (1H, m) , 3. 37 (2H, dt, J = 2.8, 11.2 Hz) , 3. 52 (2H, t, J = 6.7 Hz), 3.58 (2H, s), 3.82 (2H, t, J = 4.8 Hz), 4.01 -4.06 (2H, m), 4.19 (2H, t, J = 4.8 Hz), 4.81 - 4.88 (1H, m), 7.03 (2H, d, J = 8.8 Hz) , 7.24 - 7. 34 (3H, m) , 7. 50 - 7.56 ( 6H, m) , 7 . 67 ( 1H, s ) .
IR (KBr) v: 2944, 1653 cm 1.
Anal. Calcd. for C38HQ~N305~0.5H20: C, 71.90; H, 7.62; N, 6.62.
Found C, 71.84 H, 7.48 N, 6.71.
Working Example 30 (Production of Compound 30) In DMF (6m1) was dissolved 1-butyl-7-[4-(2-propxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.30g). Under ice-cooling, to the mixture was added thionyl chloride (0.15m1). The mixture was stirred at room temperature for 30 minutes. The solvent was evaporated under reduced pressure. In THF
(20m1) was suspended the residue, and the suspension was added dropwise to a solution of 4-[N-methyl-N-(tetrahydro-2H-pyran-4-yl)aminomethyl]aniline (0.17g) and triethylamine (0.42m1) in THF (5m1), under ice-cooling.
The mixture was stirred at room temperature overnight under nitrogen atmosphere. The solvent was evaporated under reduced solvent. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/methanol/
triethylamine). The material was dissolved in ethyl acetate-ethanol, and 6N hydrochloric acid was added to the solution. The solvent was evaporated. Diethyl ether was added to the residue, and the precipitates were filtered to give 1-butyl-7-[4-(2-propoxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide dihydrochloride (Compound 30) (0.36g) as pale yellow amorphous.
1H-NMR (8 ppm, DMSO-d6) 0. 84 - 1. 02 ( 6H, m) , 1. 30 - 1. 45 (2H, m) , 1.49 - 1.70 (4H, m) , 1.70 - 1. 95 (2H, m) , 1. 95 - 2.20 (2H, m), 2.58 (3H, d, J - 5.0 Hz), 2.80 - 2.85 (2H, m), 3.20 - 3.46 (8H, m), 3.66 - 3.84 (3H, m), 3.96 - 4.14 (3H, m) , 4. 12 (2H, t, J = 4. 7 Hz) , 4. 39 - 4. 45 (1H, m) , 6. 93 -7.02 (3H, m), 7.41 - 7.63 (7H, m), 7.81 (2H, d, J = 8.4 Hz), 10.00 (1H, s), 10.22 (1H, br).
IR (KBr) v: 2691, 2930, 2872, 1653, 1609, 1518, 1501 cml.
Anal. Calcd. for C39HS1N3O4 ~ 2HC1 ~ H20: C, 65. 35: H, 7.73; N, 5.86. Found C, 65.04; H, 7.88; N, 5.66.
Working Example 31 (Production of Compound 31) A mixture of 7-bromo-1-cyclopropyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.45g), 4-(2-butoxyethoxy)phenyl borate (0.23g), 1M potassium carbonate solution (1.5m1), ethanol (1.5m1) and toluene (25m1) was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakis(triphenylphosphine)palladium (0.05g), and the mixture was refluxed for 3 hours under argon atmosphere and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate/methanol/triethylamine) to give crude crystals, which were recrystallized to give 7-[4-(2-butoxyethoxy)phenyl]-1-cyclopropyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 31) (0.25g) as pale yellow crystals.

mp 117 - 120C.

1H-NMR (8 ppm, CDC13) 0. 55 - 0. (2H, m) , 0. 0. 93 (2H, m) , 0. 93 (3H, t, J = 7.0 Hz) , - 1.76 (8H, , 2.20 (3H, 1.21 m) s), 2.56 - 2.76 (2H, m), 2.90 (2H,t-like), 3.34 (2H, t, d J

- 8.0, 11 . 4 Hz) , 3.43 - 3. 59 m) , 3.80 (2H,t, J 5.0 (6H, =

Hz), 4.00 - 4.06 (2H, m), 4.16 (2H, Hz), 6.98 t, J = 5.0 (2H, d, J = 8. 8 Hz) , 7.25 - 7. (3H, m) , 7. 7.54 (7H, m) .
Anal. Calcd. for C39H99N3O4: C, 75.09; H, 7.92; N, 6.74.
Found C, 75.09: H, 8.14 N, 6.78.
Working Example 32 (Production of Compound 32) In DMF (4m1) was dissolved 1-benzyl-7-[4-(2-propxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.15g). Under ice-cooling, to the mixture was added thionyl chloride (0.06m1). The mixture was stirred at room temperature for 30 minutes. The solvent was evaporated under reduced pressure. In THF
(25m1) was dissolved the residue, the solution was added dropwise to a solution of 4-[N-methyl-N-(tetrahydro-2H-pyran-4-yl)aminomethyl]aniline (0.09g) and triethylamine (0.23m1) in THF (10m1), under ice-cooling. The mixture was stirred at room temperature overnight under nitrogen atmosphere. The solvent was evaporated under reduced solvent. Water was added to the mixture, the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/methanol/triethylamine).
The material was dissolved in ethyl acetate, and 4N
hydrochloric acid-ethyl acetate was added to the solution.
The solvent was evaporated to give 1-benzyl-7-[4-(2-propoxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide hydrochloride (Compound 32) (0.14g) as yellow amorphous.
1H-NMR (8 ppm, DMSO-d6) 0.87 (3H, t, J - 7.3 Hz), 1.48 -1.59 (2H, m), 1.65 - 2.15 (4H, m), 2.57 (3H, d, J = 4.8 Hz), 2.81 (2H, s), 3.25 - 3.45 (7H, m), 3.98 - 4.13 (5H, m), 4.39 - 4.46 (1H, m), 4.66 (2H, s), 6.86 (1H, d, J = 8.8 Hz), 6.99 (2H, d, J = 8.8 Hz), 7.27 - 7.57 (11H, m), 7.67 (1H, s) , 7.81 (2H, d, J = 8.4 Hz) , 10.04 (1H, s) , 10. 44 (1H, br) .
IR (KBr) v: 2963, 2868, 1655, 1607, 1518, 1499 cm 1.
Anal . Calcd. for C4zH99N3O9 ~ HC1 ~ 1 . 5Hz0: C, 69. 74; H, 7 . 39; N, 5.81. Found C, 69.35; H, 7.40; N, 5.84.
Working Example 33 (Production of Compound 33) In THF (5m1) was dissolved 1-benzyl-7-[4-(2-butoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.3g). Under ice-cooling, to the solution were added oxalyl (O.llml) and DMF (catalytic amount). The mixture was stirred at room temperature for 30 minutes, and the solvent was evaporated under reduced pressure. In THF (25m1) was dissolved the residue, the solution was added dropwise to a solution of 4-[N-methyl-N-(tetrahydro-2H-pyran-4-yl)aminomethyl]aniline (0.15g) and triethylamine (0.44m1) in THF (10 ml), under ice-cooling. The mixture was stirred at room temperature under nitrogen atmosphere and the solvent was evaporated under reduced pressure. To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol/
triethylamine) to give crude crystals, which were recrystallized from ethyl acetate-hexane to give 1-benzyl-7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 33) (0.26g) as pale yellow crystals.
mp 127 - 131°C.
1H-NMR (8 ppm, CDC13) 0. 93 (3H, t, J = 7. 1 Hz) , 1. 30 - 1.75 (8H, m), 2.21 (3H, s), 2.55 - 2.70 (1H, m), 2.85 (2H, t-like) , 3. 31 - 3. 38 (4H, m) , 3. 52 - 3. 58 (4H, m) , 3. 80 (2H, t, J = 4 . 9 Hz) , 4.01 - 4. 05 (2H, m) , 4. 16 (2H, t, J = 4. 9 Hz) , 4. 61 (2H, s) , 6. 90 (1H, d, J = 8.4 Hz) , 6. 98 (2H, d, J
- 8.8 Hz), 7.26 - 7.56 (14H, m).
IR (KBr) v: 2934, 2851, 1651, 1601, 1514, 1501 cml.
Anal. Calcd. for C43H51N304 ' 0.25H20: C, 76. 13; H, 7. 65: N, 6.19. Found C, 76.19; H, 7.55; N, 6.19.
Working Example 34 (Production of Compound 34) In THF (3m1) was dissolved 7-[4-(2-butoxyethoxy)phenyl]-1-cyclohexylmethyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.25g). Under ice-cooling, to the solution were added oxalyl chloride (0.09m1) and DMF (catalytic amount). The mixture was stirred at room temperature for 1 hour, and the solvent was evaporated under reduced pressure. In THF (25m1) was dissolved the residue, and the solution was added dropwise to a solution of 4-[N-methyl-N-(tetrahydro-2H-pyran-4-yl)aminomethyl]aniline (0.14g) and triethylamine (0.36m1) in THF (5 ml), under ice-cooling. The mixture was stirred at room temperature under nitrogen atmosphere and the solvent was evaporated under reduced pressure. To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated to give crude crystals, which were recrystallized from diethyl ether-ethyl acetate-hexane to give 7-[4-(2-butoxyethoxy)phenyl]-1-cyclohexylmethyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 34) (0.28g) as pale yellow crystals.
mp 115 - 117°C.
1H-NMR (8 ppm, CDC13) 0. 93 (3H, t, J = 7.3 Hz) , 0. 93 - 1. 84 (19H, m), 2.21 (3H, s), 2.58 - 2.66 (1H, m), 2.91 (2H, t-like) , 3. 22 (2H, d, J = 6. 6 Hz) , 3. 30 - 3. 46 (4H, m) , 3.50 - 3.58 (4H, m), 3.80 (2H, t, J = 4.9 Hz), 4.01 - 4.06 (2H, m), 4.16 (2H, t, J - 4.9 Hz), 6.91 (1H, d, J - 8.8 Hz), 6. 98 (2H, d, J = 8. 8 Hz) , 7.30 (2H, d, J = 8.4 Hz) , 7.37 -7.56 (7H, m).
IR (KBr) v: 2924, 2849, 1651, 1605, 1516, 1499 cm 1.
Anal. Calcd. for C93HS,N3O4: C, 75.96; H, 8.45; N, 6.18.
Found C, 75.93; H, 8.58; N, 6.21.
Working Example 35 (Production of Compound 35) In THF (5m1) was dissolved 7-[4-(2-butoxyethoxy)phenyl]-1-cyclopropylmethyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.35g). Under ice-cooling, to the solution were added oxalyl chloride (0.14m1) and DMF (catalytic amount). The mixture was stirred at room temperature for 1 hour, and the solvent was evaporated under reduced pressure. In THF (25m1) was dissolved the residue, and the solution was added dropwise to a solution of 4-[N-methyl-N-(tetrahydro-2H-pyran-4-yl)aminomethyl]aniline (0.20g) and triethylamine (0.56m1) in THF (10 ml), under ice-cooling. The mixture was stirred at room temperature overnight under nitrogen atmosphere and the solvent was evaporated under reduced pressure. To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/methanol/
triethylamine) to give crude crystals, which were recrystallized from ethyl acetate-hexane to give 7-[4-(2-butoxyethoxy)phenyl]-1-cyclopropylmethyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 35) (0.36g) as yellow crystals.
mp 92 - 94°C.
1H-NMR (8 ppm, CDC13) 0.26 - 0. 33 (2H, m) , 0. 60 - 0. 69 (2H, m), 0.93 (3H, t, J = 7.4 Hz), 1.05 - 1.18 (1H, m), 1.22 2.05 (8H, m) , 2.21 (3H, s) , 2. 59 - 2. 67 (1H, m) , 2. 95 (2H, t-like), 3.25 (2H, d, J - 6.2 Hz), 3.32 - 3.58 (8H, m), 3. 80 (2H, t, J = 5. 0 Hz) , 3. 93 - 4. 18 (4H, m) , 6. 95 - 7. 00 (3H, m), 7.29 (2H, d, J = 8.8 Hz), 7.41 - 7.58 (7H, m).
IR (KBr) v: 3289, 2940, 2870, 1651, 1607, 1516, 1499 cml.
Anal. Calcd. for Cq0H51N3~9 ~ C. 75. 32; H, 8 . 06; N, 6. 59.

Found C, 75.21; H, 8.12: N, 6.49.
Working Example 36 (Production of Compound 36) In THF (5m1) was dissolved 1-cyclopropylmethyl-7-[4-(2-propoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.25g). Under ice-cooling, to the solution were added oxalyl chloride (O.llml) and DMF
(catalytic amount). The mixture was stirred at room temperature for 1 hour, and the solvent was evaporated under reduced pressure. In THF (25m1) was dissolved the residue, and the solution was added dropwise to a solution of 4-[N-methyl-N-(tetrahydro-2H-pyran-4-yl)aminomethyl]aniline (0.14g) and triethylamine (0.41m1) in THF (5m1), under ice-cooling. The mixture was stirred at room temperature overnight under nitrogen atmosphere and the solvent was evaporated under reduced pressure.
To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/methanol/triethylamine), which was dissolved in ethyl acetate. To the solution was added 4N hydrochloric acid-ethyl acetate, and the solvent was evaporated to give 1-cyclopropylmethyl-7-[4-(2-propoxyethoxy)phenyl]-N-[4-[[N-methyl-N-tetrahydro-2H-pyran-4-yl]amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide dihydrochloride (Compound 36) (0.32g) as pale yellow amorphous.
1H-NMR (8 ppm, DMSO-d6) 0. 29 - 0. 31 (2H, m) , 0. 54 - 0. 57 (2H, m) , 0. 88 (2H, .t, J = 7.5 Hz) , 1.06 - 1.13 (1H, m) , 1.45 -1.63 (2H, m), 1.70 - 2.20 (4H, m), 2.57 (3H, d, J = 4.8 Hz), 2.89 (2H, br), 3.25 - 3.46 (9H, m), 3.69 - 3.74 (2H, m), 4. 10 - 4. 14 (5H, m) , 4. 37 - 4. 45 (1H, m) , 7. 00 (2H, d, J =
8.8 Hz), 7.03 - 7.11 (1H, m), 7.44 - 7.59 (6H, m), 7.68 (1H, s), 7.81 (2H, d, J = 8.6 Hz), 10.07 (1H, s), 10.63 (1H, br).
Working Example 37 (Production of Compound 37) In THF (5m1) was dissolved 7-[4-(2-butoxyethoxy)phenyl]-1-cyclobutylmethyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.25g). Under ice-cooling, to the solution were added oxalyl chloride (O.lml) and DMF (catalytic amount). The mixture was stirred at room temperature for 1 hour, and the solvent was evaporated under reduced pressure. In THF (25m1) was dissolved the residue, the solution was added dropwise to a solution of 4-[N-methyl-N-(tetrahydro-2H-pyran-4-yl)aminomethyl]aniline (0.13g) and triethylamine (0.4m1) in THF (5m1), under ice-cooling. The mixture was stirred at room temperature overnight under nitrogen atmosphere and the solvent was evaporated under reduced pressure.
To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/methanol/triethylamine), which was dissolved in ethyl acetate. To the solution was added 4N hydrochloric acid-ethyl acetate, and the solvent was evaporated to give 7-[4-(2-butoxyethoxy)phenyl]-1-cyclobutylmethyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide dihydrochloride (Compound 37) (0.27g) as pale yellow amorphous.
1H-NMR (8 ppm, DMSO-d6) 0.89 (3H, t, J - 7.1 Hz), 1.24 -1.58 (4H, m), 1.73 - 2.15 (1H, m), 2.57 (3H, d, J = 4.8 Hz), 2.60 - 2.85 (3H, m), 3.20 - 3.49 (10H, m), 3.96 - 4.13 (5H, m), 4.38 - 4.44 (1H, m), 6.97 - 7.02 (3H, m), 7.40 - 7.63 (7H, m) , 7.80 (2H, d, J = 8.8 Hz) , 10.02 (1H, s) , 10.41 (1H, s) .
Anal. Calcd. for CQ1H53N3O4~2HC1~1.5H20: C, 65.50; H, 7.78; N, 5.59. Found C, 65.51; H, 7.77; N, 5.24.
Working Example 38 (Production of Compound 38) In DMF (6m1) was dissolved 1-phenyl-7-[4-(2-propoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.2g). Under ice-cooling, to the mixture was added thionyl chloride (0.08m1). The mixture was stirred at room temperature for 30 minutes. The solvent was evaporated under reduced pressure. In THF
(20m1) was suspended the residue, the suspension was added dropwise to a solution of 4-[N-methyl-N-(tetrahydro-2H-pyran-4-yl)aminomethyl]aniline (0.12g) and triethylamine (0.31m1) in THF (5m1), under ice-cooling.
The mixture was stirred at room temperature overnight under nitrogen atmosphere. The solvent was evaporated under reduced pressure. Water was added to the mixture, the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated, the residue was purified with silica gel column chromatography (ethyl acetate/methanol/
triethylamine), which was dissolved in ethyl acetate-ethanol, 4N hydrochloric acid-ethyl acetate was added to the solution, and the solvent was evaporated to give 1-phenyl-7-[4-(2-propoxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide hydrochloride (Compound 38) (0.17g) as yellow crystals.
mp 223 - 224° C.
1H-NMR (8 ppm, DMSO-d6 ) 0 . 8 8 ( 3H, t, J - 7 . 3 Hz ) , 1. 4 5 1.60 (2H, m), 1.70 - 1.95 (2H, m), 1.95 - 2.15 (2H, m.), 2.58 (3H, d, J = 4.8 Hz), 2.84 (2H, br), 3.22 - 3.46 (4H, m), 3.72 (2H, t, J = 4.7 Hz), 3.75 - 4.12 (5H, m), 4.15 (2H, t, J = 4.7 Hz) , 4.39 - 4.46 (1H, m) , 6.80 - 6. 90 (1H, m) , 6.98 - 7.07 (4H, m), 7.20 - 7.30 (3H, m), 7.47 - 7.57 (4H, m), 7.65 (2H, d, J - 8.8 Hz), 7.79 (2H, d, J - 8.8 Hz), 7.85 (1H, s) , 9. 96 (1H, br) , 10.07 (1H, s) .
IR (KBr) v: 2961, 2928, 2863, 1651, 1520, 1495 cm 1.
Anal . Calcd. for C41H9,N3O9 ~ HCl ~ 0 . 5H20: C, 71. 23; H, 7 . 14; N, 6.08. Found C, 71.56; H, 7.17; N, 6.18.
Working Example 39 (Production of Compound 39) In THF (5m1) was dissolved 7-[4-(2-butoxyethoxy)phenyl]-1-phenyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.25g). Under ice-cooling, to the solution were added oxalyl chloride (O.lml) and DMF (catalytic amount). The mixture was stirred at room temperature for 1 hour, and the solvent was evaporated under reduced pressure. In THF (25m1) was suspended the residue, the suspension was added dropwise to a solution of 4-[N-methyl-N-(tetrahydro-2H-pyran-4-yl)aminomethyl]aniline (0.13g) and triethylamine (0.38m1) in THF (5m1), under ice-cooling. The mixture was stirred at room temperature overnight under nitrogen atmosphere and the solvent was evaporated under reduced pressure.
To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/methanol/triethylamine) to give 7-[4-(2-butoxyethoxy)phenyl]-1-phenyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 39) (0.21g) as yellow amorphous.
1H-NMR (8 ppm, CDC13) 0. 93 (3H, t, J = 7. 3 Hz) , 1.27 - 1. 49 (2H, m), 1.55 - 1.74 (6H, m), 2.19 (3H, s), 2.58 - 2.66 (1H, m), 2.93 (2H, t, J = 4.8 Hz), 3.36 (2H, dt, J = 3.2, 10.8 Hz), 3.52 - 3.59 (4H, m), 3.81 (2H, t, J - 5.0 Hz), 3.89 (2H, t, J = 4 . 8 Hz) , 4. 00 - 4. 06 (2H, m) , 4. 17 (2H, t, J =
5.0 Hz), 6.88 - 7.02 (5H, m), 7.21 - 7.30 (4H, m), 7.41 (1H, dd, J = 2.2, 8.6 Hz), 7.48 - 7.53 (6H, m), 7.64 (1H, d, J =
2.2 Hz) .
IR (KBr) v: 2953, 2934, 2847, 1653, 1595, 1520, 1495 cml.
Anal. Calcd. for C42H49N3O9 ~ 0.25H20: C, 75.93; H, 7.51; N, 6.32. Found C, 75.80: H, 7.40; N, 6.30.
Working Example 40 (Production of Compound 40) In THF (5m1) was dissolved 7-[4-(2-butoxyethoxy)phenyl]-1-(3-methoxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.15g). Under ice-cooling, to the solution were added oxalyl chloride (0.06m1) and DMF (catalytic amount). The mixture was stirred at room temperature for 30 minutes, and the solvent was evaporated under reduced pressure. In THF
(30m1) was dissolved the residue, and the solution was added dropwise to a solution of 4-[N-methyl-N-(tetrahydro-2H-pyran-4-yl)aminomethyl]aniline (0.07g) and triethylamine (0.2m1) in THF (5m1), under ice-cooling.
The mixture was stirred at room temperature overnight under nitrogen atmosphere and the solvent was evaporated under reduced pressure. To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/methanol/
triethylamine) to give crude crystals, which were recrystallized from ethyl acetate-hexane to give 7-[4-(2-butoxyethoxy)phenyl]-1-(3-methoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 40) (O.llg) as pale yellow crystals.
mp 94 - 97°C.
1H-NMR (8 ppm, CDC13)0. 93 (3H, t, 7.4 Hz) , 1.27 - 1.76 J =

(8H, m), 2.20 (3H, s), 2.58 - 2.69 (1H,m), 2.95 (2H, t-like), 3.36 J = 3.4, 11.5 ), 52 - 3.59 (4H, (2H, dt, Hz 3. m), 3.76 (3H, s), 3.76 - 3.87 (4H, m), 4.00- 4.06 (2H, m), 4.17 (2H, t, J = 4.9 Hz), 6.43 - 6.62 (3H,m), 7.00 (2H, d, J = 8.8 Hz), 7.14 - 7.30 (3H, m), 7.40 - 7.54 (7H, m), 7.64 ( 1H, d, J = 1. 8 Hz ) .
IR (KBr) v: 2955, 2845, 1661, 1595, 1516, 1493 cml.
Anal. Calcd. for C93H51N3O5: C, 74.86; H, 7.45; N, 6.09.
Found C, 74.52; H, 7.66; N, 6.19.
Working Example 41 (Production of Compound 41) In THF (5m1) was dissolved 7-[4-(2-butoxyethoxy)phenyl]-1-(4-methoxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.2g). Under ice-cooling, to the solution were added oxalyl chloride (0.08m1) and DMF (catalytic amount). The mixture was stirred at room temperature for 1 hour, and the solvent was evaporated under reduced pressure. In THF (20m1) was dissolved the residue, and the solution was added dropwise to a solution of 4-[N-methyl-N-(tetrahydro-2H-pyran-4-yl)aminomethyl]aniline (0.1g) and triethylamine (0.3m1) in THF (5m1), under ice-cooling. The mixture was stirred at room temperature overnight under nitrogen atmosphere and the solvent was evaporated under reduced pressure. To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/methanol/

triethylamine) to give 7-[4-(2-butoxyethoxy)phenyl]-1-(4-methoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 41) (0.22g) as yellow amorphous.
1H-NMR (8 ppm, CDC13) 0. 93 (3H, t, J = 7. 1 Hz) , 1.26 - 1.48 (2H, m) , 1. 54 - 1 . 74 ( 6H, m) , 2 . 20 ( 3H, s ) , 2 . 58 - 2 . 66 ( 1H, m), 2.90 (2H, t-like), 3.37 (2H, dt, J - 2.2, 12.7 Hz), 3.52 - 3.58 (4H, m), 3.78 - 3.83 (7H, m), 4.01 - 4.06 (2H, m), 4.16 (2H, t, J = 4.9 Hz), 6.85 - 7.05 (7H, m), 7.26 -7.34 (2H, m), 7.46 - 7.59 (7H, m).
Working Example 42 (Production of Compound 42) In THF (5m1) was dissolved 7-[4-(2-butoxyethoxy)phenyl]-1-(4-propoxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.2g). Under ice-cooling, to the solution were added oxalyl chloride (0.05m1) and DMF (catalytic amount). The mixture was stirred at room temperature for 1 hour, and the solvent was evaporated under reduced pressure. In THF (20m1) was dissolved the residue, and the solution was added dropwise to a solution of 4-[N-methyl-N-(tetrahydro-2H-pyran-4-yl)aminomethyl]aniline (O.llg) and triethylamine (0.3m1) in THF (5m1), under ice-cooling. The mixture was stirred at room temperature overnight under nitrogen atmosphere and the solvent was evaporated under reduced pressure. To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/methanol/
triethylamine) to give 7-[4-(2-butoxyethoxy)phenyl]-1-(4-propoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 42) (0.2g) as yellow amorphous.
1H-NMR (8 ppm, CDC13) 0 . 93 ( 3H, t, J = 7 . 3 Hz ) , 1. 04 ( 3H, t, J = 7.3 Hz), 1.34 - 1.48 (2H, m), 1.54 - 1.86 (8H, m), 2.20 (3H, s) , 2. 58 - 2. 69 (1H, m) , 2. 88 (2H, t-like) , 3. 36 (2H, dt, J = 3.4, 11.0 Hz), 3.52 - 3.58 (5H, m), 3.78 - 3.83 (4H, m) , 3. 90 (2H, t, J = 10. 1 Hz) , 4. 00 - 4. 17 (4H, m) , 6.84 -7.03 (7H, m), 7.26 - 7.33 (2H, m), 7.45 - 7.61 (7H, m).
IR (KBr) v: 2936, 2872, 1651, 1607, 1495 cml.
Working Example 43 (Production of Compound 43) In THF (5m1) was dissolved 7-[4-(2-butoxyethoxy)phenyl]-1-(3,4-methylenedioxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.25g).
Under ice-cooling, to the solution were added oxalyl chloride (O.lml) and DMF (catalytic amount). The mixture was stirred at room temperature for 1 hour, and the solvent was evaporated under reduced pressure. In THF
(30m1) was dissolved the residue, and the solution was added dropwise to a solution of 4-[N-methyl-N-(tetrahydro-2H-pyran-4-yl)aminomethyl]aniline (0.13g) and triethylamine (0.35m1) in THF (5m1), under ice-cooling.
The mixture was stirred at room temperature overnight under nitrogen atmosphere and the solvent was evaporated under reduced pressure. To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/methanol/
triethylamine) to give 7-[4-(2-butoxyethoxy)phenyl]-1-(3,4-methylenedioxyphenyl)-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 43) (0.28g) as yellow amorphous.
1H-NMR (b ppm, CDC13) 0.93 (3H, t, J = 7.3 Hz), 1.22 - 1.48 (4H, m), 1.54 - 1.74 (4H, m), 2.20 (3H, s), 2.58 - 2.67 (1H, m), 2.91 (2H, t-like), 3.37 (2H, dt, J - 3.0, 11.2 Hz), 3.52 - 3. 59 (4H, m) , 3. 78 - 3.83 (4H, m) , 4.01 - 4. 19 (4H, m) , 5. 95 (2H, s) , 6. 50 (1H, dd, J = 2.2, 8.4 Hz) , 6. 61 (1H, d, J = 2.2 Hz), 6.76 (1H, d, J = 8.4 Hz), 6.97 - 7.03 (3H, m), 7.26 - 7.37 (3H, m), 7.46 - 7.59 (7H, m).
IR (KBr) v: 2951, 2872, 1651, 1607, 1514, 1487 cm 1.
Working Example 44 (Production of Compound 17) In phosphorus oxychloride (25m1) was dissolved 1-(N-acetylglycyl)-7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.5g). The solution was heated to stir at room temperature for 7 hours and at 50°C for 2 hours, and the solvent was evaporated. To the residue was added sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified with basic silica gel column chromatography (ethyl acetate/hexane). The resulting crude crystals were recrystallized from ethyl acetate-hexane to give 7-[4-(2-butoxyethoxy)phenyl]-1-(2-methyloxazol-5-yl)-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 44) (0.26g) as pale yellow crystals.
mp 125 - 128°C.
1H-NMR (b ppm, CDC13) 0. 93 (3H, t, J = 7.3 Hz) , 1.22 - 1.48 (2H, m), 1.54 - 1.76 (6H, m), 2.20 (3H, s), 2.41 (3H, s), 2.55 - 2.70 (1H, m), 2.96 (2H, t-like), 3.36 (2H, dt, J =
2.6, 11.0 Hz), 3.52 - 3.58 (4H, m), 3.72 (2H, t-like), 3.80 (2H, t, J = 4.8 Hz) , 4.00 - 4.06 (2H, m) , 4. 15 (2H, t, J =
4.8 Hz) , 6. 33 (1H, s) , 6. 98 (2H, d, J = 8.8 Hz) , 7.08 (1H, d, J = 8.4 Hz), 7.26 - 7.56 (8H, m), 7.76 (1H, s).
IR (KBr) v: 2936, 2870, 1651, 1516, 1495 cnll.
Anal. Calcd. for C4oH48N905: C, 72.26: H, 7.28; N, 8.43.
Found C, 72.16 H, 7.10 N, 8.51.
Working Example 45 (Production of Compound 45) In DMF (20m1) were suspended 7-[4-(2-butoxyethoxy)phenyl]-1-(2-methylthiazol-4-yl)-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.13g), 4-[N-methyl-N-(tetrahydro-2H-pyran-4-yl)aminomethyl]aniline dihydrochloride (0.1g) and 1-hydroxybenzotriazole (0.06g).
Under ice-cooling, to the suspension were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.15g), triethylamine (0.18m1) and 4-dimethylaminopyridine (catalytic amount), and the mixture was stirred at room temperature overnight, which was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified with silica gel column (ethyl acetate/methanol/triethylamine) to give crude crystals, which were recrystallized from ethyl acetate-diethyl ether-hexane to give 7-[4-(2-butoxyethoxy)phenyl]-1-(2-methylthiazol-4-yl)-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 45) (0.087g) as pale yellow crystals.
mp 115 - 123°C.
1H-NMR (8 ppm, CDC13) 0. 93 (3H, t, J = 7. 3 Hz) , 1. 30 - 1.45 (2H, m), 1.55 - 1.76 (6H, m), 2.21 (3H, s), 2.55 - 2.75 (1H, m), 2.67 (3H, s), 2.94 (2H, t-like), 3.36 (2H, dt, J = 2.6, 11.2 Hz), 3.52 - 3.59 (4H, m), 3.81 (2H, t, J = 4.9 Hz), 4.01 - 4.19 (6H, m), 5.93 (1H, s), 7.00 (2H, d, J = 8.8 Hz), 7.31 (1H, s), 7.43 - 7.60 (9H, m).
IR (KBr) v: 2932, 2870, 2843, 1659, 1597, 1526, 1518, 1495 cm 1.
Working Example 46 (Production of Compound 46) In DMF (20m1) were suspended 7-[4-(2-butoxyethoxy)phenyl]-1-(4-sulfamoylphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.15g), 4-[N-methyl-N-(tetrahydro-2H-pyran-4-yl)aminomethyl]aniline dihydrochloride (O.llg) and 1-hydroxybenzotriazole (0.06g). Under ice-cooling, to the suspension were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.16g), triethylamine (0.2m1) and 4-dimethylaminopyridine (catalytic amount), and the mixture was stirred at room temperature overnight. The solvent was evaporated, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified with silica gel column (ethyl acetate/methanol/triethylamine) to give crude crystals, which were recrystallized from ethyl acetate-hexane to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-1-(4-sulfamoylphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 46) (0.085g) as yellow crystals.
mp 108 - 111°C.
1H-NMR (8 ppm, CDC13) 0.93 (3H, t, J = 7.2 Hz) , 1.33 - 1.48 (2H, m), 1.54 - 1.75 (6H, m), 2.15 (3H, s), 2.57 - 2.67 (1H, m) , 2. 78 - 2. 94 (2H, m) , 3. 33 (2H, t, J = 10. 3 Hz) , 3. 46 -3.58 (4H, m), 3.78 - 3.82 (4H, m), 3.97 - 4.02 (2H, m), 4.06 - 4. 14 (2H, m) , 6.78 (2H, d, J = 9.2 Hz) , 6. 97 (2H, d, J = 8.8 Hz), 7.19 - 7.29 (3H, m), 7.36 - 7.63 (9H, m), 8.16 ( 1H, s ) .
Working Example 47 (Production of Compound 47) In DMF (25m1) were suspended 7-[4-(2-butoxyethoxy)phenyl]-1-(N,N-dimethyl-4-sulfamoylphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.3g), 4-[N-methyl-N-(tetrahydro-2H-pyran-4-yl)aminomethyl]aniline dihydrochloride (0.19g) and 1-hydroxybenzotriazole (0.07g). Under ice-cooling, to the suspension were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.15g), triethylamine (0.37m1) and 4-dimethylaminopyridine (catalytic amount), and the mixture was stirred at room temperature overnight. The solvent was evaporated, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified with silica gel column (ethyl acetate/methanol/triethylamine) to give crude crystals, which were recrystallized from ethyl acetate-hexane to give 7-[4-(2-butoxyethoxy)phenyl]-1-(N,N-dimethyl-4-sulfamoylphenyl)-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 47) (0.12g) as colorless crystals.
mp 94 - 98°C.
1H-NMR (8 ppm, CDC13) 0. 94 (3H, t, J = 7.1 Hz) , 1.22 - 1. 74 (8H, m), 2.20 (3H, s), 2.55 - 2.70 (1H, m), 2.70 (6H, s), 3. 02 (2H, t-like) , 3. 36 (2H, dt, J = 2. 6, 11. 0 Hz) , 3. 53 -3.60 (4H, m), 3.82 (2H, t, J = 5.0 Hz), 3.85 - 4.14 (4H, m), 4.18 (2H, t, J = 5.0 Hz), 6.96 (2H, d, J = 8.8 Hz), 7.03 (2H, d, J = 8.8 Hz) , 7.30 (2H, d, J = 8.4 Hz) , 7. 37 - 7. 63 ( 9H, m) , 7 . 70 ( 1H, d, J = 2 . 2 Hz ) .
Working Example 48 (Production of Compound 48) In THF (7m1) was dissolved 7-[4-(2-butoxyethoxy)phenyl]-1-(N-methyl-4-sulfamoylphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.4g). Under ice-cooling, to the solution were added oxalyl chloride (0.19m1) and DMF (catalytic amount). The mixture was stirred at room temperature for 1 hour, and the solvent was evaporated under reduced pressure. In THF (25m1) was dissolved the residue, and the solution was added dropwise to a suspension of 4-[N-methyl-N-(tetrahydro-2H-pyran-4-yl)aminomethyl]aniline dihydrochloride(0.28g) and triethylamine (0.5m1) in THF (5m1), under ice-cooling.
The mixture was stirred at room temperature under nitrogen atmosphere for 1 hour and the solvent was evaporated under reduced pressure. To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified with basic silica gel column chromatography (ethyl acetate) to give crude crystals, which were recrystallized from ethyl acetate-hexane to give 7-[4-(2-butoxyethoxy)phenyl]-1-(N-methyl-4-sulfamoylphenyl)-N-[4-[[N-methyl-N-tetrahydro-2H-pyran-4-yl]amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 48) (0.28g) as pale yellow crystals.
mp 96 - 99°C.
1H-NMR (8 ppm, CDC13) 0. 93 (3H, t, J = 7. 3 Hz) , 1.29 - 1.71 (8H, m), 2.17 (3H, s), 2.59 (3H, d, J - 4.0 Hz), 2.60 -2.70 (1H, m), 2.95 (2H, t-like), 3.35 (2H, dt, J - 2.6, 11. 4 Hz) , 3. 52 - 3. 59 (4H, m) , 3. 79 - 3. 88 (4H, m) , 3. 99 -4.17 (4H, m), 4.66 (1H, br), 6.86 (2H, d, J = 8.8 Hz), 6.99 (2H, d, J = 8.4 Hz), 7.23 - 7.66 (12H, m), 8.05 (1H, d, J =
9.6 Hz) .
IR (KBr) v: 2942, 2853, 1661, 1590, 1495 cml.
Reference Example 98 Propionyl chloride (1.0m1) was added dropwise to a suspension of methyl 7-(2-propoxyethoxy)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.2g) and potassium carbonate (2.2g) in DMF (lOml) under ice-cooling. The mixture was stirred at room temperature overnight under nitrogen atmosphere, and poured into water, which was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give methyl 1-propionyl-7-(2-propoxyethoxy)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.2g) as pale yellow oil.
1H-NMR (8 ppm, CDC13 ) 0 . 95 ( 3H, t, J = 7 . 3 Hz ) , 1. 05 ( 3H, t, J = 7.3 Hz), 1.57 - 1.75 (2H, m), 2.09 - 2.20 (1H, m), 2.41 - 2.53 (1H, m), 2.75 - 2.84 (2H, m), 2.88 - 3.10 (1H, m), 3.52 (2H, t, J = 6.7 Hz), 3.80 - 3.83 (5H, m), 4.18 (2H, t, J = 4.6 Hz), 4.75 - 4.80 (1H, m), 7.03 (2H, d, J = 8.8 Hz), 7.24 (1H, d, J = 8.4 Hz), 7.48 - 7.55 (3H, m), 7.65 (1H, d, J = 1.8 Hz), 7.73 (1H, s).
IR (neat) v: 2948, 2874, 1713, 1661 cml.
Reference Example 99 In methanol (25m1) and THF (25m1) was dissolved methyl 1-propionyl-7-(2-propoxyethxy)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.2g), and to the solution was added 1N sodium hydroxide solution (5m1). The mixture was stirred at room temperature overnight, concentrated.
neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated to give 1-propionyl-7-(2-propoxyethoxy)-2,3-dihydro-1H-1-benzazepine-4 carboxylic acid (0.2g) as colorless crystals.
1H-NMR (8 ppm, CDC13) 0 . 95 ( 3H, t, J 7 . 3 Hz ) , 1.
= 07 ( 3H, t, J = 7.5 Hz), 1.57 - 1.75 (2H, m), 2.12 - 2.22 (1H, m), 2.43 - 2.55 (1H, m), 2.78 - 2.88 (2H, m), 3.00 - 3.10 (1H, m), 3.53 (2H, t, J = 6.8 Hz), 3.83 (2H, t, J = 5.0 Hz), 4.19 (2H, t, J = 5.0 Hz), 4.78 - 4.80 (1H, m), 7.03 (2H, J
d, =

8.6 Hz), 7.26 (1H, d, J - 8.2 Hz), 7.51 - 7.56 (3H, m), 7. 67 (1H, d, J = 1.4 Hz) , 7.83 (1 H, .
s) IR (KBr) v: 2940, 2876, 1705 cml.

Reference Example 100 In 1,2-dichloroethane (20) were dissolved methyl 7-bromo-2,3-dihydro-1H-1-benzazepine-4-carboxylate (1.0g), n-butylaldehyde (1.3m1) and acetic acid (0.41m1), and to the solution was added sodium triacetoxyborohydride (3.8g). The mixture was stirred at room temperature overnight, poured into water, neutralized with sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give methyl 7-bromo-1-butyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.9g) as pale yellow oil.
1H-NMR (8 ppm, CDC13) 0. 96 (3H, t, J = 7.2 Hz) , 1.27 - 1.45 (2H,.m), 1.56 - 1.72 (2H, m), 2.79 (2H, t, J - 4.2 Hz), 3.19 - 3.31 (4H, m), 3.80 (3H, s), 6.69 (1H, d, J = 8.8 Hz), 7.23 (1H, dd, J = 2.5, 8.8 Hz), 7.42 (1H, d, J = 2.5 Hz), 7.57 (1H, s).
Reference Example 101 A mixture of methyl 7-bromo-1-butyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.45g), 4-(2-propoxyethoxy)phenyl borate (0.66g), 1M potassium carbonate solution (4m1), ethanol (4m1) and toluene (25m1) was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakis(triphenylphosphine)palladium (0.12g), and the mixture was refluxed overnight under argon atmosphere and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give methyl 1-butyl-7-[4-(2-propoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.5g) as pale yellow oil.
1H-NMR (8 ppm, CDC13) 0. 91 - 1.01 (6H, m) , 1.30 - 1.45 (2H, m), 1.57 - 1.73 (4H, m), 2.80 (2H, t, J = 4.6 Hz), 3.25 -3.37 (4H, m), 3.51 (2H, t, J = 6.1 Hz), 3.78 - 3.83 (5H, m), 4.16 (2H, t, J = 4.9 Hz), 6.87 (1H, d, J = 8.4 Hz), 6.97 (2H, d, J = 8.8 Hz), 7.37 - 7.51 (4H, m), 7.76 (1H, s).
IR (neat) v: 2959, 2928, 2870, 1698, 1607, 1501 crnl.
Reference Example 102 In methanol (25m1) and THF (25m1) was dissolved methyl 1-butyl-7-[4-(2-propoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.5g). To the solution was added 1N sodium hydroxide solution (17m1), and the mixture was heated to stir at 50°C for 5 hours, concentrated, neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated to give 1-butyl-7-[4-(2-propoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.38g) as yellow crystals.
mp 176 - 177°C.
1H-NMR (8 ppm, CDC13) 0. 91 - 1.02 (6H, m) , 1. 35 - 1.46 (2H, m), 1.60 - 1.74 (4H, m), 2.84 (2H, t-like), 3.32 - 3.39 (4H, m), 3.52 (2H, t, J - 6.8 Hz), 3.81 (2H, t, J - 5.1 Hz), 4.17 (2H, t, J = 5.1 Hz), 6.88 (1H, d, J = 9.2 Hz), 6.98 (2H, d, J = 8.8 Hz), 7.40 - 7.53 (4H, m), 7.88 (1H, s).
IR (KBr) v: 2959, 2932, 2872, 1669, 1607, 1501 cml.
Anal. Calcd. for Cz6H33N04: C, 73.73; H, 7.85; N, 3.31. Found C, 73.42; H, 7.86; N, 3.25.
Reference Example 103 To cyclopropylamine (50m1) was added dropwise t-butyl 4-bromobutyrate (33.5g) at 40°C. To the mixture was added sodium iodide (22.6g), and the mixture was refluxed overnight. The solvent was evaporated, and to the residue was added water. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by distillation under reduced pressure to give t-butyl N-cyclopropyl-4-aminobutyrate (12.6g) as colorless oil.
by 85 - 90°C/5 mm.
1H-NMR (8 ppm, CDC13) 0.27 - 0.47 (4H, m), 1.45 (9H, s), 1. 69 - 1 . 84 (2H, m) , 2. 08 - 2. 15 (1H, m) , 2.26 (2H, t, J =
7.3 Hz), 2.71 (2H, t, J = 7.3 Hz).
Reference Example 104 5-bromo-2-fluorobenzaldehyde (20g), t-butyl N-cyclopropyl-4-aminobutyrate (14.5g), sodium carbonate (13.8g), water (70m1) and DMSO (70m1) were heated at 80°C
for 5 days and at 110°C for 3 days, which was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give t-butyl N-(4-bromo-2-formylphenyl)-N-cyclopropyl-4-aminobutyrate (6.4g) as red oil.
1H-NMR (b ppm, CDC13) 0. 45 - 0. 52 (2H, m) , 0.72 - 0. 78 (2H, m), 1.41 (9H, s), 1.88 - 1.98 (2H, m), 2.17 (2H, t, J = 7.1 Hz), 2.66 - 2.73 (1H, m), 3.29 (2H, t, J = 7.5 Hz), 7.13 (1H, d, J = 8.8 Hz), 7.53 (1H, dd, J = 2.6, 8.8 Hz), 7.84 (1H, d, J = 2.6 Hz), 10.09 (1H, s).
Reference Example 105 In THF(l0ml) was dissolved t-butyl N-(4-bromo-2-formylphenyl)-N-cyclopropyl-4-aminobutyrate (1g). To the solution was added potassium t-butoxide (0.59g), and the mixture was heated at 55°C for 1.5 hours. The solvent was evaporated, which was extracted with water. The aqueous layer was washed with ethyl acetate, and neutralized by addition of 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated to give 7-bromo-1-cyclopropyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.44g) as yellow crystals.
mp 225 - 230°C (dec.).
1H-NMR (b ppm, CDC13) 0.42 - 0. 50 (2H, m) , 0. 80 - 0.84 (2H, m) , 2. 60 - 2.80 (3H, m) , 3.24 - 3. 34 (2H, m) , 7. 13 (1H, d, J = 8.8 Hz), 7.38 (1H, dd, J = 2.4, 8.8 Hz), 7.45 (1H, s), 7.53 (1H, d, J = 2.4 Hz), 12.39 (1H, br).
Anal. Calcd. for C14H14BrN02: C, 54.56: H, 4.58; N, 4.55.
Found C, 54.20; H, 4.60; N, 4.30.
Reference Example 106 In THF (15m1) was dissolved 7-bromo-1-cyclopropyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.4g).
Under ice-cooling, to the solution were added oxalyl chloride (0.26m1) and DMF (catalytic amount), and the mixture was stirred at room temperature for 30 minutes.
The solvent was evaporated under reduced pressure. In THF (30m1) was dissolved the residue, and the solution was added dropwise to a solution of 4-[N-methyl-N-(tetrahydro-2H-pyran-4-yl)aminomethyl]aniline (0.34g) and triethylamine (0.9m1) in THF (5m1) under ice-cooling.
The mixture was stirred under nitrogen atmosphere at room temperature overnight. The solvent was evaporated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified with silica gel column chromatography (ethyl acetate/methanol/
triethylamine) to give 7-bromo-1-cyclopropyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.55g) as yellow crystals.
mp 133 - 136°C.
1H-NMR (8 ppm, CDC13) 0. 50 - 0. 58 (2H, m) , 0. 79 - 0. 88 (2H, m), 1.63 - 1.76 (4H, m), 2.20 (3H, s), 2.58 - 2.71 (2H, m), 2.86 (2H, t, J = 8.8 Hz) , 3. 37 (2H, dt, J = 3.0, 11. 4 Hz) , 3.46 (2H, t, J = 4.9 Hz), 3.56 (2H, s), 4.01 - 4.07 (2H, m), 7.08 (1H, d, J = 8.8 Hz), 7.14 (1H, s), 7.26 - 7.32 (2H, m), 7 . 37 ( 1H, d, J - 2 . 6 Hz ) , 7 . 52 ( 2H, d, J = 8 . 8 Hz ) , 7 . 57 ( 1H, s ) .
Anal. Calcd. for Cz,H32BrN302: C, 63.53 H, 6.32; N, 8.23.
Found C, 63.30: H, 6.26 N, 8.15.

Reference Example 107 In DMF (3m1) was dissolved methyl 7-bromo-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.3g), and the solution was added dropwise to a suspension of 60s sodium hydride (0.05g) in DMF (1m1) under ice-cooling. The mixture was stirred under nitrogen atmosphere for 10 minutes. Benzyl bromide (0.15m1) was added thereto, and the mixture was heated at 45°C for 4 hours. The mixture was poured into water, and extracted with ethyl acetate.
The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give methyl 1-benzyl-7-bromo-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.3g) as yellow oil.
1H-NMR (8 ppm, CDC13) 2.75 (2H, t, J = 4. 9 Hz) , 3.26 (2H, t, J = 4.9 Hz), 3.80 (3H, s), 4.52 (2H, s), 6.67 (1H, d, J =
8. 8 Hz) , 7. 19 (1H, dd, J = 2.4, 8.8 Hz) , 7.22 - 7. 45 (6H, m), 7.47 (1H, d, J = 2.4 Hz), 7.63 (1H, s).
IR (neat) v: 1703 cml.
Reference Example 108 A mixture of methyl 1-benzyl-7-bromo-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.3g), 4-(2-propoxyethoxy)phenyl borate (0.24g), 1M potassium carbonate solution (2.5m1), ethanol (2.5m1) and toluene (25m1) was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakis(triphenylphosphine)palladium (0.04g), and the mixture was refluxed under argon atmosphere overnight.
The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give methyl 1-benzyl-7-[4-(2-propoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.27g) as yellow oil.
1H-NMR (8 ppm, CDC13) 0. 94 (3H, t, J = 7.5 Hz) , 1.58 - 1.70 (2H, m) , 2. 77 (2H, t, J = 4. 6 Hz) , 3. 32 (2H, t, J = 4. 6 Hz) , 3.51 (2H, t, J = 6.8 Hz), 3.78 - 3.83 (2H, m), 3.81 (3H, s), 4.07 - 4.18 (2H, m), 4.59 (2H, s), 6.87 (1H, d, J = 8.4 Hz), 6. 98 (2H, d, J = 8.8 Hz) , 7.26 - 7.41 (6H, m) , 7. 47 (2H, d, J = 8.8 Hz), 7.56 (1H, d, J = 2.2 Hz), 7.83 (1H, s).
IR (neat) v: 3027, 2874, 1701, 1499 cml.
Reference Example 109 In methnol (lOml) and THF (lOml) was dissolved methyl 1-benzyl-7-[4-(2-propoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.27g). To the solution was added 1N sodium hydroxide solution (lOml), and the mixture was stirred at room temperature overnight and concentrated, which was neutralized with 1N
hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated to give 1-benzyl-7-[4-(2-propoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.16g) as yellow crystals.
mp 139 - 142°C.
1H-NMR (8 ppm, CDC13) 0. 94 . (3H, t, J = 7. 3 Hz) , 1. 59 - 1.70 (2H, m), 2.80 (2H, t, J = 4.6 Hz), 3.34 (2H, t, J = 4.6 Hz), 3. 52 (2H, t, J = 6. 8 Hz) , 3. 78 - 3. 84 (2H, m) , 4. 14 - 4 . 19 (2H, m) , 4. 61 (2H, s) , 6.87 (1H, d, J = 8.8 Hz) , 6. 98 (2H, d, J = 8.8 Hz), 7.26 - 7.49 (8H, m), 7.57 (1H, d, J = 2.2 Hz), 7.95 (1H, s).
IR (KBr) v: 2934, 2870, 1674, 1607, 1501 cm 1.
Anal. Calcd. for CZ9H31NO4: C, 76.12; H, 6.83; N, 3.06. Found C, 75.77; H, 6.95; N, 3.15.
Reference Example 110 In 1,2-dichloroethane (7m1) were dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.4g) and benzaldehyde (0.43g). To the solution was added sodium triacetoxyborohydride (0.43g), and the mixture was stirred under nitrogen atmosphere at room temperature overnight, poured into water, neutralized with sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated to give methyl 1-benzyl-7-[4-(2-butoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.49g) as oil.
1H-NMR (b ppm, CDC13) 0. 93 (3H, t, J = 7.3 Hz) , 1. 30 - 1. 48 (2H, m), 1.54 - 1.68 (2H, m), 2.77 (2H, t, J - 4.7 Hz), 3.31 (2H, t, J = 4.7 Hz), 3.55 (2H, t, J = 6.6 Hz), 3.78 -3.82 (5H, m) , 4. 15 (2H, t, J = 4. 8 Hz) , 4. 59 (2H, s) , 6.86 (1H, d, J = 8. 8 Hz) , 6. 97 (2H, d, J = 8.8 Hz) , 7.26 - 7. 68 (7H, m), 7.82 - 7.91 (3H, m).
IR (neat) v: 2934, 2870, 1703, 1607, 1501 cml.
Reference Example 111 In methnol (25m1) and THF (25m1) was dissolved methyl 1-benzyl-7-[4-(2-butoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.49g). To the solution was added 1N sodium hydroxide solution (lOml), and the mixture was heated at 50°C overnight and concentrated, which was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated to give 1-benzyl-7-[4-(2-butoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.47g) as yellow crystals.

mp 133 - 138°C.
1H-NMR (8 ppm, CDC13) 0. 93 (3H, t, J = 7.4 Hz) , 1. 34 - 1.45 (2H, m), 1.54 - 1.65 (2H, m), 2.80 (2H, br), 3.34 (2H, br), 3.56 (2H, t, J = 6.6 Hz), 3.80 (2H, t, J = 5.0 Hz), 4.16 (2H, t, J = 5.0 Hz), 4.61 (2H, s), 6.88 (1H, d, J = 8.8 Hz), 6.98 (2H, d, J = 8.8 Hz), 7.26 - 7.49 (8H, m), 7.57 (1H, d, J = 2.2 Hz), 7.94 (1H, s).
IR (KBr) v: 2957, 2934, 2867, 1674, 1609, 1501 cml.
Anal. Calcd. for C3oH33N04: C, 76.41; H, 7.05: N, 2.97. Found C, 76.06; H, 7.15; N, 2.68.
Reference Example 112 In 1,2-dichloroethane (5m1) were dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.3g) and cyclohexanecarboaldehyde (0.43g):
To the solution was added sodium triacetoxyborohydride (0.43g), and the mixture was stirred under nitrogen atmosphere at room temperature for 3.5 hours, poured into water, neutralized with sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated to give methyl 7-[4-(2-butoxyethoxy)phenyl]-1-cyclohexylmethyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.37g) as pale yellow oil.
1H-NMR (b ppm, CDC13) 0.89 - 1.81 (15H, m), 0.93 (3H, t, J =

7.3 Hz), 2.81 (2H, t, J = 4.2 Hz), 3.19 (2H, d, J = 6.6 Hz), 3.29 (2H, t, J = 4. 8 Hz) , 3. 55 (2H, t, J = 6. 6 Hz) , 3. 78 3.82 (5H, m) , 4. 15 (2H, t, J = 4. 9 Hz) , 6.87 (1H, d, J
8.8 Hz), 6.97 (2H, d, J - 8.8 Hz), 7.36 - 7.51 (4H, m), 7.76 (1H, s).
IR (neat) v: 2930, 2849, 1699, 1607, 1499 cml.
Reference Example 113 In methanol (25m1) and THF (25m1) was dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-1-cyclohexylmethyl 2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.37g). To the solution was added 1N sodium hydroxide solution (7.5m1), and the mixture was stirred at room temperature overnight and concentrated, which was neutralized with 1N
hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated to give 7-[4-(2-butoxyethoxy)phenyl]-1-cyclohexylmethyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.32g) as yellow crystals.
mp 124 125C.
-1H-NMR ppm, CDC13) 0.90 - 1.85(15H, m), 0.93 (3H, t, J
(8 =

7. 2 Hz) 2. (2H, t-like) , (2H, d, J = 6. 6 Hz) , 3.
, 83 3.22 32 (2H, t-like), 3.56 (2H, t, J 6.6 Hz), 3.81 (2H, t, J
= -5.0 Hz), 4.16 (2H, t, J = 5.0 , 6.89 (1H, d, J = 8.8 Hz), Hz) 6.98 (2H, d, = 8.8 Hz), 7.39 7.53 (4H, m), 7.88 (1H, J - s).

IR (KBr) v: 2926, 1674, 1607, 1499 cml.
Anal. Calcd. for C3oH39NO4: C, 75.44; H, 8.23; N, 2.93. Found C, 75.46; H, 8.23: N, 2.96.
Reference Example 114 In 1,2-dichloroethane (7m1) were dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.4g) and cyclopropanecarboaldehyde (0.3g).
To the solution was added sodium triacetoxyborohydride (0.43g), and the mixture was stirred under nitrogen atmosphere at room temperature overnight, poured into water, neutralized with sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated to give methyl 7-[4-(2-butoxyethoxy)phenyl]-1-cyclopropylmethyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.45g) as yellow oil.
1H-NMR (8 ppm, CDC13) 0.24 - 0. 32 (2H, m) , 0. 58 - 0. 67 (2H, m), 0.93 (3H, t, J = 7.3 Hz), 1.08 - 1.15 (1H, m), 1.34 1.49 (2H, m), 1.55 - 1.68 (2H, m), 2.86 (2H, t, J = 4.4 Hz), 3.23 (2H, d, J = 6.6 Hz), 3.39 (2H, t, J = 4.7 Hz), 3.55 (2H, t, J = 6. 6 Hz) , 3.73 - 3. 83 (5H, m) , 4. 11 - 4. 18 (2H, m), 6.92 - 7.01 (3H, m), 7.38 - 7.53 (4H, m), 7.77 (1H, s).
IR (neat) v: 2953, 2930, 2870, 1699, 1607, 1499 cml.
Reference Example 115 In methanol (25m1) and THF (25m1) was dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-1-cyclopropylmethyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.45g). To the solution was added 1N sodium hydroxide solution (lOml), and the mixture was stirred at room temperature overnight and concentrated, which was neutralized with 1N
hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated to give 7-[4-(2-butoxyethoxy)phenyl]-1-cyclopropylmethyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.42g) as yellow crystals.
mp 152 - 155°C.
1H-NMR (8 ppm, CDC13) 0.25 - 0. 33 (2H, m) , 0. 59 - 0. 68 (2H, m), 0.93 (3H, t, J = 7.3 Hz), 1.05 - 1.20 (1H, m), 1.30 -1.49 (2H, m), 1.55 - 1.69 (2H, m), 2.87 (2H, t, J = 4.6 Hz), 3.25 (2H, d, J = 6.4 Hz), 3.42 (2H, t, J = 4.6 Hz), 3.56 (2H, t, J = 6.6 Hz), 3.81 (2H, t, J = 5.0 Hz), 4.16 (2H, t, J = 5.0 Hz), 6.93 - 7.00 (3H, m), 7.40 - 7.54 (4H, m), 7.89 (1H, s) .
IR (KBr) v: 2959, 2936, 2868, 1669, 1607, 1501 aril.
Anal. Calcd. for CZ,H33N04: C, 74.45; H, 7.64; N, 3.22. Found C, 74.27; H, 7.45; N, 3.21.
Reference Example 116 In 1,2-dichloroethane (5m1) were dissolved methyl 7-[4-(2-propoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.3g) and cyclopropanecarboaldehyde (0.22g). To the solution was added sodium triacetoxyborohydride (0.33g), and the mixture was stirred under nitrogen atmosphere at room temperature for 4 hours, poured into water, neutralized with sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated to give methyl 1-cyclopropylmethy-7-[4-(2-propoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.34g) as yellow oil.
1H-NMR (8 ppm, CDC13) 0.24 - 0. 32 (2H, m) , 0. 58 - 0. 67 (2H, m) , 0 . 94 ( 3H, t, J = 7 . 5 Hz ) , 1. 05 - 1. 15 ( 1H, m) , 1. 60 1.74 (2H, m), 2.85 (2H, t, J - 4.6 Hz), 3.23 (2H, d, J
6.6 Hz), 3.39 (2H, t, J = 4.6 Hz), 3.51 (2H, t, J = 6.7 Hz), 3.79 - 3.84 (5H, m), 4.16 (2H, t, J = 5.0 Hz), 6.91 - 7.01 (3H, m), 7.38 - 7.52 (4H, m), 7.77 (1H, s).
IR (neat) v: 2936, 2872, 1699, 1607, 1499 cnll.
Reference Example 117 In methanol (25m1) and THF (25m1) was dissolved methyl 1-cyclopropylmethy-7-[4-(2-propoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.34g). To the solution was added 1N sodium hydroxide solution (7.5m1), and the mixture was stirred at room temperature overnight, heated at 50°C for 1 hour, concentrated, which was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated to give 1-cyclopropylmethyl-7-[4-(2-propoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.30g) as yellow crystals.
mp 154 - 156°C.
1H-NMR (8 ppm, CDC13) 0. 25 - 0. 33 (2H, m) , 0. 59 - 0. 68 (2H, m) , 0 . 95 ( 3H, t, J = 7 . 3 Hz ) , 1 . 05 - 1. 18 ( 1H, m) , 1. 56 -1.74 (2H, m), 2.87 (2H, t, J = 4.8 Hz), 3.25 (2H, d, J =
6.2 Hz), 3.42 (2H, t, J = 4.8 Hz), 3.51 (2H; t, J = 6.8 Hz), 3. 81 (2H, t, J = 4 . 9 Hz) , 4. 17 (2H, t, J = 4. 9 Hz) , 6. 93 -7.00 (3H, m), 7.40 - 7.53 (4H, m), 7.88 (1H, s).
IR (KBr) v: 2963, 1669, 1518 cml.
Anal. Calcd. for C26H31N04: C, 74.08; H, 7.41; N, 3.32. Found C, 74.03; H, 7.53; N, 3.27.
Reference Example 118 In 1,2-dichloroethane (7m1) were dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.4g) and cyclobutanecarboaldehyde (0.5g).
To the solution was added sodium triacetoxyborohydride (0.43g), and the mixture was stirred under nitrogen atmosphere at room temperature for 4 hours, poured into water, neutralized with sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated to give methyl 7-[4-(2-butoxyethoxy)phenyl]--1-cyclobutylmethyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.47g) as yellow oil.
1H-NMR (8 ppm, CDC13) 0. 93 (3H, t, J = 7. 3 Hz) , 1.34 - 1. 45 (2H, m), 1.54 - 2.13 (8H, m), 2.70 - 2.81 (3H, m), 3.26 (2H, t, J = 4.8 Hz) , 3.38 (2H, d, J = 7.4 Hz) , 3.55 (2H, t, J =
6.6 Hz), 3.78 - 3.83 (5H, m), 4.16 (2H; t, J - 4.9 Hz), 6 . 87 ( 1H, d, J = 8 . 8 Hz ) , 6 . 97 ( 2H, d, J = 8 . 8 Hz ) , 7 . 37 -7.51 (4H, m), 7.75 (1H, s) Reference Example 119 In methanol (25m1) and THF (25m1) was dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-1-cyclobutylmethyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.47g). To the solution was added 1N sodium hydroxide solution (lOml), and the mixture was heated at 50°C overnight, concentrated, neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated to give 7-[4-(2-butoxyethoxy)phenyl]-1-cyclobutylmethyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.40g) as yellow crystals.
mp 110 - 112°C.
1H-NMR (b ppm, CDC13) 0 . 93 ( 3H, t, J = 7 . 3 Hz ) , 1. 30 - 2 . 00 (8H, m), 2.00 - 2.15 (2H, m), 2.71 - 2.80 (3H, m), 3.29 (2H, t, J = 4 . 8 Hz ) , 3 . 39 ( 2H, d, J = 7 . 0 Hz ) , 3 . 55 ( 2H, t, J =
6.6 Hz), 3.80 (2H, t, J = 5.0 Hz), 4.16 (2H, t, J = 5.0 Hz), 6.88 (1H, d, J = 8.8 Hz) , 6. 98 (2H, d, J = 8.8 Hz) , 7. 39 7.51 (4H, m), 7.85 (1H, s).
Anal. Calcd. for Cz$H35NO9: C, 74 . 80: H, 7 . 85: N, 3. 12 . Found C, 74.51; H, 7.92; N, 2.98.
Reference Example 120 In dichloromethane (15m1) were dissolved methyl 7 bromo-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.5g) and copper pivalate (0.05g). To the solution was added triphenylbismuth diacetate (1.1g), and the mixture was stirred at room temperature overnight, poured into water, stirred, neutralized with 1N sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give methyl 7-bromo-1-phenyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.27g) as yellow crystals.

mp 104 - 106°C.
1H-NMR (8 ppm, CDC13) 2.82 (2H, t, J = 4.4 Hz) , 3. 76 (2H, t, J = 4.4 Hz), 3.78 (3H, s), 6.90 - 7.00 (4H, m), 7.22 - 7.30 (3H, m), 7.58 (1H, d, J = 2.2 HZ), 7.62 (1H, S).
IR (KBr) v: 2949, 1705 cm 1.
Anal. calcd for C1gH16BrN02: C, 60.35; H, 4.50; N, 3.91.
Found C, 60.16; H, 4.28; N, 3.85.
Reference Example 121 A mixture of methyl 7-bromo-1-phenyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.27g), 4-(2-propoxyethoxy)phenyl borate (0.23g), 1M potassium carbonate solution (3m1), ethanol (3m1) and toluene (25m1) was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakis(triphenylphosphine)palladium (0.04g), and the mixture was refluxed under argon atmosphere overnight, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give methyl 1-phenyl-7-[4-(2-propoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.26g) as yellow crystals.
mp 117 - 119°C.

1H-NMR ppm,CDC13) 0. (3H, t, J = 7.5 Hz) 1. - 1.71 (8 95 , 57 (2H, m), 2.85(2H, t, J 4.6 Hz), 3.52 (2H, J 6.8 Hz), = t, =

3.79 (3H, s), 3.79 - 3.84 (4H, m), 4.18 (2H, J 5.0 Hz), t, =

6. 87 - 03 -7 . 30 ( 3H, m) , ( dd, J
7 ( 7 . 40 1H, =
. 5H, m) , .

2.2, 8.4 Hz),7.51 (2H, (1H,d, J
d, J = 8.8 =
Hz), 7.64 2.2 Hz), 7.80(1H, s).

IR (KBr) v: 1705, 1493 cm 1.
Anal. Calcd. for Cz9H31NO9: C, 76.12; H, 6.83; N, 3.06. Found C, 75.81; H, 6.75; N, 2.77.
Reference Example 122 In methanol (25m1) and THF (25m1) was dissolved methyl 1-phenyl-7-[4-(2-propoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.23g). To the solution was added 1N sodium hydroxide solution (lOml), and the mixture was heated at 50°C overnight, concentrated, neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated to give 1-phenyl-7-[4-(2-propoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.23g) as yellow crystals.
mp 135 - 139°C.
1H-NMR (b ppm, CDC13) 0 . 95 ( 3H, t, J = 7 . 5 Hz ) , 1. 60 - 1. 71 (2H, m) , 2. 86 (2H, t-like) , 3. 52 (2H, t, J = 6. 7 Hz) , 3. 80 - 3.85 (4H, m), 4.18 (2H, t, J = 4.8 Hz), 6.90 - 7.04 (5H, m), 7.17 (1H, d, J = 8.5 Hz), 7.23 - 7.31 (2H, m), 7.40 (1H, dd, J = 2.2, 8.5 Hz), 7.51 (2H, d, J = 8.8 Hz), 7.65 (1H, d, J = 2.2 Hz), 7.90 (1H, s).
IR (KBr) v: 2963, 2936, 2872, 1674, 1609, 1593, 1493 cm 1.
Anal. Calcd. for CZ8H29N09: C, 75.82; H, 6.59; N, 3.16. Found C, 75.43; H, 6.37; N, 3.10.
Reference Example 123 In dichloromethane (lOml) were dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.5g) and copper pivalate (0.07g). To the solution was added triphenylbismuth diacetate (0.78g), and the mixture was stirred at room temperature overnight, poured into 3N hydrochloric acid, stirred, neutralized with 1N sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give methyl 7-[4-(2-butoxyethoxy)phenyl]-1-phenyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.42g) as yellow crystals.
mp 80 - 82°C.
1H-NMR (8 ppm, CDC13) 0. 94 (3H, t, J = 7. 1 Hz) , 1.31 - 1.49 (2H, m), 1.56 - 1.69 (2H, m), 2.85 (2H, t, J - 4.4 Hz), 3.56 (2H, J = 6.6 Hz), 3.79 3.84 (7H, m), 4.17 (2H, t, - t, J = 4.9 Hz),6.87 - 7.02 (5H, m), 7.16 - 7.30 (3H, m), 7.40 ( 1H, dd, 2 . 2, 8 . 8 Hz ) ( d, J = 8 . 4 Hz ) J = , 7 . 51 2H, , 7 . 64 (1H, d, J = 2.2 Hz) , 7.80 (1H, s) .
IR (KBr) v: 2955, 2868, 1705, 1593, 1495 cml.
Anal. Calcd. for C3oH33NO4: C, 76.41; H, 7.05; N, 2.97. Found C, 76.30; H, 7.17; N, 2.90.
Reference Example 124 In methanol (25m1) and THF (25m1) was dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-1-phenyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.37g). To the solution was added 1N sodium hydroxide solution (7.5m1), and the mixture was stirred at room temperature overnight, concentrated, neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated to give 7-[4-(2-butoxyethoxy)phenyl]-1-phenyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.27g) as yellow crystals.
mp 129 - 131°C.
1H-NMR (8 ppm, CDC13) 0. 94 (3H, t, J = 7.2 Hz) , 1.34 - 1.49 (2H, m), 1.55 - 1.69 (2H, m), 2.86 (2H, t, J - 4.4 Hz), 3.56 (2H, t, J = 6.6 Hz), 3.79 - 3.84 (4H, m), 4.17 (2H, t, J = 4.8 Hz), 6.90 - 7.04 (5H, m), 7.17 (1H, d, J = 8.6 Hz), 7.23 - 7.31 (2H, m), 7.40 (1H, dd, J = 2.2, 8.6 Hz), 7.50 ( 2H, d, J = 7 . 2 Hz ) , 7 . 64 ( 1H, d, J = 1. 8 Hz ) , 7 . 90 ( 1H, s ) .
IR (KBr) v: 2957, 2870, 1674, 1609, 1593, 1493 cm 1.
Anal. Calcd. for CZ9H31N09: C, 76.12; H, 6.83; N, 3.06. Found C, 76.18 H, 6.85 N, 3.21.
Reference Example 125 In dichloromethane (7m1) were dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.25g) and copper pivalate (0.04g). To the solution was added tri(3-methoxyphenyl)bismuth diacetate (1.5g), and the mixture was stirred at room temperature overnight, poured into 3N hydrochloric acid, stirred, neutralized with 1N sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give methyl 7-[4-(2-butoxyethoxy)phenyl]-1-(3-methoxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.16g) as yellow oil.
1H-NMR (8 ppm, CDC13) 0. 94 (3H, t, J = 7.2 Hz) , 1. 34 - 1. 45 (2H, m), 1.55 - 1.65 (2H, m), 2.86 (2H, t, J - 4.8 Hz), 3.56 (2H, t, J = 6. 6 Hz) , 3. 75 (3H, s) , 3.79 (3H, s) , 3.79 - 3. 84 ( 4H, m) , 4 . 17 (2H, t, J = 4 . 9 Hz ) , 6. 42 - 6. 60 ( 3H, m),7.00 (2H, d, J = 8.8 Hz), 7.11 - 7.26 (2H, m), 7.41 (1H, dd,J = 2.2, 8.4 Hz), 7.51 (2H, d, J = 8.8 Hz), 7.64 (1H, d, J 2.2 Hz), 7.78(1H, s).
=

IR (neat) v: 2955, 2932, 2870, 1705 cm 1.
Reference Example 126 In methanol (25m1) and THF (25m1) was dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-1-(3-methoxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.16g). To the solution was added 1N sodium hydroxide solution (2.8m1), and the mixture was heated at 50°C overnight, concentrated, neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated to give 7-[4-(2-butoxyethoxy)phenyl]-1-(3-methoxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.16g) as yellow crystals.
mp 154 - 156C.

1H-NM R (8 ppm, CDC13) 0. (3H, t, = 7. 4 Hz) , 1.34 1.

(2H, m) , 1. 55 - 1. (2H, m) , 2. (2H, 65 87 (2H, t-like) , 3. 56 t, J = 6.6 Hz), 3.76 (3H, s), 3.79 3.84 (4H, m), 4.17(2H, -t, J = 4 . 8 Hz) , - 61 (3H, 7. 00 (2H, d, J 8.
6. 45 6. m) , = 8 Hz), 7.13 - 7.24 (2H, m), 7.42 (1H, dd, J = 2.2, 8.4 Hz), 7.51 (2H, d, J = 8.8 Hz), 7.64 (1H, d, J = 2.2 Hz), 7.88 (1H, s) .

Anal. Calcd. for C3oH33N~s: C, 73.90; H, 6.82; N, 2.87. Found C, 73.73; H, 6.72; N, 2.83.
Reference Example 127 In dichloromethane (lOml) were dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.3g) and copper pivalate (0.06g). To the solution was added tri(4-methoxyphenyl)bismuth diacetate (1.5g), and the mixture was stirred at room temperature overnight, poured into 3N hydrochloric acid, stirred, neutralized with 1N sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give methyl 7-[4-(2-butoxyethoxy)phenyl]-1-(4-methoxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.38g) as yellow oil.
1H-NMR (8 ppm, CDC13) 0. 93 (3H, t, J = 7.2 Hz) , 1. 30 - 1.45 (2H, m), 1.55 - 1.65 (2H, m), 2.82 (2H, t, J - 4.4 Hz), 3.56 (2H, t, J = 6.6 Hz), 3.72 - 3.83 (10H, m), 4.16 (2H, t, J = 4.4 Hz), 6.85 - 6.91 (3H, m), 6.96 - 7.04 (4H, m), 7.30 (1H, dd, J = 2.2, 8.4 Hz) , 7.48 (2H, d, J = 8. 8 Hz) , 7.59 (1H, d, J = 2.2 Hz), 7.82 (1H, s).
IR (neat) v: 2955, 1705, 1609, 1508, 1491 cml.

Reference Example 128 In methanol (25m1) and THF (25m1) was dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-1-(4-methoxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.38g). To the solution was added 1N sodium hydroxide solution (8m1), and the mixture was heated at 50°C overnight, concentrated, neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated to give 7-[4-(2-butoxyethoxy)phenyl]-1-(4-methoxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid(0.27g) as yellow crystals.

mp 164 - 166C.

1H-NMR (8 ppm, CDC13) 0. (3H, t, J = 7 Hz) , 1. 1.
93 . 1 34 - 49 (2H, m) , 1. 54 - 1. (2H, m) , 2 . 83 (2H, (2H, 68 t-like) , 3.

t, J = 6.0 Hz) , 3.74 - 83 (7H, m) , (2H, t, J 4.
3. 4. 16 = 9 Hz), 6.85 - 7.06 (7H, m), 7.31 (1H, dd, = 2.2, 8.4 Hz), J

7.47 (2H, d, J = 8.8 Hz) 7.59 (1H, d, = 2.2 Hz) 7.
, J , 92 (lH,s).
IR (KBr) v: 2957, 2928, 2868, 1674, 1609, 1508, 1493 cml.
Anal. Calcd. for C3oH33N05: C, 73.90 H, 6.82 N, 2.87. Found C, 73.87; H, 6.89; N, 2.70.
Reference Example 129 In dichloromethane (7m1) were dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.2g) and copper pivalate (0.04g). To the solution was added tri(4-propoxyphenyl)bismuth diacetate (1.1g), and the mixture was stirred at room temperature overnight, poured into 3N hydrochloric acid, stirred, neutralized with 1N sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give methyl 7-[4-(2-butoxyethoxy)phenyl]-1-(4-propoxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.25g) as yellow oil.
1H-NMR (8 ppm, CDC13) 0.93 (3H, t, J = 7.3 Hz), 1.04 (3H, t, J = 7.5 Hz), 1.34 - 1.45 (2H, m), 1.54 - 1.68 (2H, m), 1.75 - 1 . 86 (2H, m) , 2. 81 (2H, t, J = 4. 4 Hz) , 3. 55 (2H, t, J =
6.6 Hz), 3.71 - 3.83 (7H, m), 3.90 (2H, t, J - 6.6 Hz), 4. 14 - 4. 18 (2H, m) , 6.84 - 6. 90 (3H, m) , 6. 96 - 7.02 (4H, m), 7.29 (1H, dd, J = 2.2, 8.4 Hz), 7.48 (2H, d, J = 6.6 Hz), 7.58 (1H, d, J = 2.2 Hz), 7.82 (1H, s).
IR (neat) v: 2957, 2934, 2870, 1705, 1622, 1609, 1507, 1489 cm 1.
Reference Example 130 In methanol (50m1) and THF (50m1) was dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-1-(4-propoxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.25g). To the solution was added 1N sodium hydroxide solution (5m1), and the mixture was heated at 50°C overnight, concentrated, neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated to give 7-[4-(2-butoxyethoxy)phenyl]-1-(4-propoxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.21g) as yellow crystals.
mp 182 - 185°C.
1H-NMR (8 ppm, CDC13 ) 0 . 93 ( 3H, t, J = 7 . 1 Hz ) , 1. 04 ( 3H, t, J = 7.6 Hz), 1.30 - 1.49 (2H, m), 1.54 - 1.68 (2H, m), 1.76 - 1.86 (2H, m), 2.83 (2H, t-like), 3.55 (2H, t, J = 6.6 Hz), 3.76 (2H, t-like), 3.80 (2H, t, J = 5.0 Hz), 3.91 (2H, t, J
- 6. 6 Hz) , 4. 16 (2H, t, J = 5. 0 Hz) , 6. 84 - 7. 05 (7H, m) , 7.30 (1H, dd, J = 2.2, 8.6 Hz), 7.47 (2H, d, J = 8.8 Hz), 7.58 (1H, d, J = 2.2 Hz), 7.92 (1H, s).
IR (KBr) v: 2959, 2934, 2872, 1669, 1609, 1508, 1493 cml.
Anal. Calcd. for C32H3,N05: C, 74.54; H, 7.23; N, 2.72. Found C, 74.19; H, 7.32; N, 2.87.
Reference Example 131 In dichloromethane (7m1) were dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.25g) and copper pivalate (0.05g). To the solution was added tri(3,4-methylenedioxyphenyl)bismuth diacetate (1.3g), and the mixture was stirred at room temperature overnight, poured into 3N hydrochloric acid, stirred, neutralized with 1N sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give methyl 7-[4-(2-butoxyethoxy)phenyl]-1-(3,4-methylenedioxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.3g) as yellow oil.
1H-NMR (8 ppm, CDC13) 0 . 93 ( 3H, t, J = 7 . 2 Hz ) , 1. 30 - 1. 4 9 (2H, m), 1.55 - 1.68 (2H, m), 2.82 (2H, t, J - 4.6 Hz), 3. 56 (2H, t, J = 6. 6 Hz) , 3. 73 (2H, t, J = 4. 9 Hz) , 3.79 -3. 84 (5H, m) , 4. 17 (2H, t, J = 4. 9 Hz) , 5. 94 (2H, s) , 6.49 (1H, dd, J = 2.2, 8.4 Hz) , 6. 60 (1H, d, J = 2.2 Hz) , 6. 75 ( 1H, d, J = 8 . 4 Hz ) , 6 . 94 - 7 . 02 ( 3H, m) , 7 . 33 ( 1H, dd, J =
2.2, 8.4 Hz), 7.48 (2H, d, J = 8.8 Hz), 7.59 (1H, d, J -2.2 Hz), 7.80 (1H, s).
IR (neat) v: 2955, 2932, 2870, 1703, 1609, 1485 cml.
Reference Example 132 In methanol (25m1) and THF (25m1) was dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-1-(3,4-methylenedioxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.3g). To the solution was added 1N sodium hydroxide solution (6m1), and the mixture was refluxed for 2 hours, concentrated, neutralized with 1N
hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated to give 7-[4-(2-butoxyethoxy)phenyl]-1-(3,4-methylenedioxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.26g) as yellow crystals.
mp 145 - 148°C.
1H-NMR (8 ppm, CDC13) 0. 93 (3H, t, J = 7.3 Hz) , 1. 30 - 1.49 (2H, m), 1.55 - 1.68 (2H, m), 2.84 (2H, t, J - 5.2 Hz), 3.56 (2H, t, J = 6.6 Hz), 3.74 (2H, t, J = 5.2 Hz), 3.81 (2H, t, J = 5.0 Hz), 4.17 (2H, t, J = 5.0 Hz), 5.95 (2H, s), 6.52 (1H, dd, J = 2.2, 8.4 Hz), 6.62 (1H, d, J = 2.2 Hz), 6.76 (1H, d, J = 8.4 Hz), 6.92 - 7.01 (3H, m), 7.34 (1H, dd, J = 2.2, 8.4 Hz) , 7.48 (2H, d, J = 8. 8 Hz) , 7.59 (1H, d, J
- 2.2 Hz), 7.91 (1H, s).
IR (KBr) v: 2932, 2867, 1678, 1609, 1486 cml.
Anal. Calcd. for C30H31N06: C, 71.84; H, 6.23; N, 2.79. Found C, 71.61; H, 6.19; N, 2.62.
Reference Example 133 In THF (25m1) were dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (1g) and pyridine (2m1). Under ice-cooling, to the solution was added dropwise chloroacetyl chloride (1m1). The mixture was stirred under nitrogen atmosphere at room temperature for 1 hour, and the solvent was evaporated. To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give methyl 7-[4-(2-butoxyethoxy)phenyl]-1-chloroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (1.1g) as pale yellow oil.
1H-NMR (8 ppm, CDC13 ) 0 . 94 ( 3H, t, J = 7 . 2 Hz ) , 1. 30 - 1. 69 (4H, m), 2.78 - 3.13 (3H, m), 3.56 (2H, t, J - 6.6 Hz), 3.80 - 3.84 (5H, m), 3.93 (1H, d, J = 12.8 Hz), 4.11 - 4.20 (3H, m), 4.76 - 7.84 (1H, m), 7.03 (2H, d, J - 8.8 Hz), 7.34 (1H, d, J = 8.4 Hz), 7.50 - 7.58 (3H, m), 7.68 (1H, d, J = 1.8 Hz), 7.74 (1H, s).
Reference Example 134 In DMF (30m1) was dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-1-chloroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (1.1g). To the solution was added sodium azide (0.23g), and the mixture was heated at 65°C for 1 hour, poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give pale yellow oil (0.8g), which was dissolved in THF (50m1). To the solution were added triphenylphosphine (1.1g) and water (catalytic amount), and the mixture was heated at 50°C for 1.5 hours. The solvent was evaporated and, to the residue was added water, and the mixture was extracted with ethyl acetate.
The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified with silica gel column chromatography (ethyl acetate/methanol/
triethylamine) to give pale yellow oil (0.7g), which was dissolved in THF (15m1). To the solution were added pyridine (0.7m1) and acetic anhydride (0.25m1), and the mixture was stirred under nitrogen atmosphere at room temperature overnight. The solvent was evaporated and, to the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated to give methyl 1-(N-acetylglycyl)-7-[4-(2-butoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.67g) as colorless crystals.
mp 130 - 134°C.
1H-NMR (8 ppm, CDC13) 0. 94 (3H, t, J = 7.3 Hz) , 1.26 - 1. 69 (4H, m), 2.01 (3H, s), 2.76 - 3.12 (3H, m), 3.51 - 3.62 (3H, m), 3.78 - 3.83 (5H, m), 4.16 (2H, t, J = 4.9 Hz), 4.33 (1H, dd, J = 4. 0, 18. 0 Hz) , 4 . 73 - 4. 80 (1H, m) , 6. 42 (1H, br) , 7.03 (2H, d, J = 8.8 Hz), 7.28 (1H, d, J = 7.8 Hz), 7.49 -7.56 (3H, m), 7.65 (1H, d, J = 2.2 Hz), 7.72 (1H, s).
IR (KBr) v: 3316, 2951, 2934, 2870, 1713, 1661 cml.
Anal. Calcd. for CZ8H34N206: C, 68.00; H, 6.93; N, 5.66.
Found C, 67.84; H, 6.74 N, 5.61.
Reference Example 135 In methanol (50m1) was dissolved methyl 1-(N-acetylglycyl)-7-[4-(2-butoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (1.2g). To the solution was added 1N sodium hydroxide solution (13m1), and the mixture was stirred at room temperature overnight, concentrated, neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated to give 1-(N-acetylglycyl)-7-[4-(2-butoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (1.2g) as colorless crystals.
mp 196 - 201°C.

1H-NMR ppm, CDC13) 7. Hz) , 1.26 1.
(8 0. 94 (3H, 3 - 69 t, J =

(4H, m), 2.02 (3H, 2.78 - 3.15 (3H, 3.53 - 3.62 (3H, s), m), m), 3.82 (2H, t, J 4.9 Hz), 4.19 (2H,t, J - 4.9 Hz), -4 . 36 ( dd, J = 4 18 . 0 Hz ) , - 82 ( 1H, m) 6 1H, . 0, 4 . 75 4 , .
. 53 (1H, br), 7.03 (2H, J = 8.8 Hz), 7.31(1H, d, J 8.0 d, =

Hz), 7.50 - 7.58 (3H, m), 7.67 (1H, d, = 2.2 Hz), 7.81 J

(1H, s) .
IR (KBr) v: 2951, 2872, 1669 cml.
Anal. Calcd. for C2,H32N206: C, 66.86; H, 6.75; N, 5.78.
Found C, 66.65 H, 6.73 N, 5.97.
Reference Example 136 In DMF (20m1) were suspended 1-(N-acetylglycyl)-7-[4-(2-butoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.85g), 4-[N-methyl-N-(tetrahydro-2H-pyran-4-yl)aminomethyl]aniline dihydrochloride (0.52g) and 1-hydroxybenzotriazole (0.3g). Under ice-cooling, to the suspension were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1g), triethylamine (1.7m1) and 4-dimethylaminopyridine (catalytic amount), and the mixture was stirred at room temperature overnight. The solvent was evaporated and, to the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified with basic silica gel column chromatography (ethyl acetate/methanol/triethylamine) to give 1-(N-acetylglycyl)-7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (1.1g) as pale yellow amorphous.
1H-NMR (8 ppm, CDC13) 0. 93 (3H, t, J = 7.4 Hz) , 1.25 - 1.75 (8H, m), 2.05 (3H, s), 2.19 (3H, s), 2.55 - 2.70 (1H, m), 2 . 8 6 - 3 . 14 ( 3H, m) , 3 . 37 ( 2H, dt, J = 2 . 6, 11. 0 Hz ) , 3 . 53 - 3.71 (5H, m), 3.82 (2H, t, J = 5.0 Hz), 4.01 - 4.07 (2H, m), 4.11 - 4.28 (3H, m), 4.75 - 4.81 (1H, m), 6.49 (1H, br), 7.02 (2H, d, J = 8.4 Hz) , 7.24 - 7. 33 (4H, m) , 7. 43 - 7. 61 ( 6H, m) , 8 . 09 ( 1H, s ) .
Reference Example 137 In toluene (25m1) were suspended methyl 7-[4-(2-butoxyethoxy)phenyl]-1-chloroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.75g) and thioacetamide (0.36g). The suspension was heated at 90°C for 1 hour and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give methyl 7-[4-(2-butoxyethoxy)phenyl]-1-(2-methylthiazol-4-yl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.17g) as yellow oil.
1H-NMR (8 ppm, CDC13) 0. 94 (3H, t, J = 7.2 Hz) , 1.26 - 1. 65 (4H, m) , 2. 67 (3H, s) , 2. 86 (2H, t, J = 5.3 Hz) , 3.56 (2H, t, J - 6.6 Hz), 3.80 (3H, s), 3.81 (2H, t, J - 4.9 Hz), 3.95 (2H, t, J = 5.3 Hz), 4.17 (2H, t, J = 4.9 Hz), 5.92 (1H, s) , 7. 00 (2H, d, J = 8. 8 Hz) , 7.43 (2H, s) , 7.51 (2H, d, J = 8.8 Hz), 7.62 (1H, s), 7.77 (1H, s).
Reference Example 138 In dichloromethane (15m1) was dissolved methyl 7-bromo-1-phenyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.68g). Under ice-cooling, to the solution was added dropwise chlorosulfonic acid (0.32m1). The mixture was stirred at room temperature for 30 minutes and, to the mixture was additionally added chlorosulfonic acid (0.2m1), and the mixture was stirred at room temperature for 10 minutes. The reaction solution was added dropwise to aqueous ammonia (lOml) under ice-cooling, and the mixture was stirred for 30 minutes. The solvent was evaporated and, to the residue was added hot ethyl acetate. The insolubles were filtered and the solvent in the filtrate was evaporated. The precipitated methyl 7-bromo-1-(4-sulfamoylphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.33g) was collected by filtration and washed with ethyl acetate-hexane to give the carboxylate as yellow crystals.

mp 200 - 203°C.
1H-NMR (8 ppm, CDC13) 2.89 (2H, t, J = 5. 5 Hz) , 3. 78 (3H, s) , 3.84 (2H, t, J = 5.5 Hz), 4.65 (2H, s), 6.87 (2H, d, J -9.2 Hz), 7.18 (1H, d, J = 8.4 Hz), 7.43 (1H, dd, J = 2.2, 8.4 Hz) , 7. 60 (1H, s) , 7. 68 (1H, d, J = 2.2 Hz) , 7.73 (2H, d, J = 9.2 Hz).
IR (KBr) v: 1713 cml.
Anal. Calcd. for C18H1,BrN209S: C, 49.44; H, 3.92; N, 6.41.
Found C, 49.30 H, 4.20 N, 6.04.
Reference Example 139 A mixture of methyl 7-bromo-1-(4-sulfamoylphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.31g), 4-(2-butoxyethoxy)phenyl borate (0.22g), 1M potassium carbonate solution (3m1), ethanol (5m1) and toluene (50m1) was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakis(triphenylphosphine)palladium (0.04g), and the mixture was refluxed under argon atmosphere for 3 hours and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give methyl 7-[4-(2-butoxyethoxy)phenyl]-1-(4-sulfamoylphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.34g) as yellow crystals.
mp 163 - 165°C .
1H-NMR (8 ppm, CDC13) 0.94 (3H, t, J = 7.3 Hz) , 1.35 - 1.46 (2H, m), 1.56 - 1.66 (2H, m), 2.92 (2H, t, J - 5.0 Hz), 3.57 (2H, t, J = 6.6 Hz), 3.79 (3H, s),.3.79 - 3.92 (4H, m), 4.18 (2H, t, J = 4.8 Hz), 4.73 (2H, s), 6.91 (2H, d, J -9.2 Hz), 7.03 (2H, d, J = 8.8 Hz), 7.34 (1H, d, J = 8.2 Hz), 7.50 - 7.56 (3H, m), 7.71 - 7.77 (4H, m).
IR (KBr) v: 2957, 2934, 2870, 1705, 1590, 1493 cml.
Anal. Calcd. for C3oH39N2O6S ~ 0.25H20: C, 65.43; H, 6.22: N, 5.09. Found C, 65.04; H, 6.35; N, 4.91.
Reference Example 140 In methanol (50m1) and THF (15m1) was dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-1-(4-sulfamoylphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.34g). To the solution was added 1N sodium hydroxide solution (lOml), and the mixture was refluxed for 2 hours, concentrated, neutralized with 1N
hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated to give 7-[4-(2-butoxyethoxy)phenyl]-1-(4-sulfamoylphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.3g) as yellow crystals.
mp 185 - 195°C.

1H-NMR (8 ppm, CDC13) 0. 94 (3H, t, J = 7. 1 Hz) , 1.27 - 1.46 (2H, m) , 1. 55 - 1. 66 (2H, m) , 2. 92 (2H, t-like) , 3.57 (2H, t, J = 6.6 Hz), 3.82 (2H, t, J = 4.9 Hz), 3.90 (2H, t-like), 4. 19 (2H, t, J = 4. 9 Hz) , 4. 73 (2H, s) , 6. 93 (2H, d, J -8.8 Hz), 7.03 (2H, d, J = 8.8 Hz), 7.35 (1H, d, J = 8.0 Hz), 7.52 - 7.56 (3H, m), 7.72 - 7.76 (3H, m), 7.85 (1 H s).
Anal. Calcd. for C29H32NZO6S: C, 64.91; H, 6.01; N, 5.22.
Found C, 65.08; H, 6.17: N, 5.03.
Reference Example 141 In dichloromethane (lOml) was dissolved methyl 7-bromo-1-phenyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.4g). Under ice-cooling, to the solution was added dropwise chlorosulfonic acid (0.74m1). The mixture was stirred at room temperature for 30 minutes and, to the mixture was additionally added chlorosulfonic acid (0.37m1), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was added dropwise to 2M dimethylamine solution in methanol (35m1) under ice-cooling, and the mixture was stirred overnight. The solvent was evaporated and, to the residue was added water, and the mixture was extracted with ethyl acetate.
The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated to give methyl 7-bromo-1-(N,N-dimethyl-4-sulfamoylphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.37g) as yellow crystals.
mp 210 - 213°C.
1H-NMR (8 ppm, CDC13) 2.69 (6H, s), 2.90 {2H, t, J = 5.1 Hz), 3.79 (3H, s), 3.84 {2H, t, J - 5.1 Hz), 6.89 {2H, d, J =
9.2 Hz), 7.21 (1H, d, J = 8.4 Hz), 7.94 (1H, dd, J = 2.2, 8.4 Hz), 7.57 - 7.62 (3H, m), 7.68 {1H, d, J = 2.2 Hz).
IR (KBr) v: 2955, 1709, 1595, 1582, 1501, 1483 cml.
Anal. Calcd. for CzoHzlBrNzO9S: C, 51.62; H, 4.55; N, 6.02.
Found C, 51.60; H, 4.55; N, 5.78.
Reference Example 142 A mixture of methyl 7-bromo-1-(N,N-dimethyl-4-sulfamoylphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.35g), 4-(2-butoxyethoxy)phenyl borate (0.19g), 1M potassium carbonate solution (2m1), ethanol (2m1) and toluene {50m1) was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakis(triphenylphosphine)palladium (0.04g), and the mixture was refluxed under argon atmosphere for 6 hours and extracted with ethyl acetate.
The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give methyl 7-[4-(2-butoxyethoxy)phenyl]-1-(N,N-dimethyl-4-sulfamoylphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.35g) as colorless crystals.
mp 150 - 153C.

1H-NMR (8 ppm, CDC13) 94 ( 3H, t, J = 7 . 3 Hz ) , 1.
0 . 1. 35 - 66 (4H, m), 2.69 (6H, s), 2.93 (2H, t-like), 3.57 (2H, J
t, =

6. 6 Hz) , 3. (3H, s) 3.80 - 3.89 (4H, m) , 4. 19 t, 80 , (2H; J

- 5.0 Hz) , 6. 4 (2H, J = 8.8 Hz) , 7.03 (2H, d, J 8.8 9 d, =

Hz), 7.38 (1H, d, J - 8.4 Hz), 7.51 - 7.62 (5H, m), 7.71 (1H, s) , 7.78 (1H, s) .

IR (KBr) v: 2959, 2868, 1709, 1590, 1495 cml.
Anal. Calcd. for C3zH3gN2O6S: C, 66.41; H, 6.62; N, 4.84.
Found C, 66.25; H, 6.89; N, 4.76.
Reference Example 143 In methanol (50m1) and THF(50m1) was dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-1-(N,N-dimethyl-4-sulfamoylphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.34g). To the solution was added 1N sodium hydroxide solution (lOml), and the mixture was stirred at room temperature at 60°C for 1 hour, concentrated, neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated to give 7-[4-(2-butoxyethoxy)phenyl]-1-(N,N-dimethyl-4--sulfamoylphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.33g) as yellow crystals.
mp 236 - 238°C.
1H-NMR (b ppm, CDC13) 0. 94 (3H, t, J = 7.1 Hz) , 1.30 - 1.50 (2H, m), 1.56 - 1.66 (2H, m), 2.69 (6H, s), 2.93 (2H, t like) , 3.57 (2H, t, J = 6. 6 Hz) , 3.83 (2H, t, J = 4.8 Hz) , 3.91 (2H, t-like), 4.19 (2H, J = 4.8 Hz), 6.96 (2H,d, t, J

- Hz) 7.03 (2H, d, J = 8. Hz) , 7.39 (1H, d, =
9.2 , 8 J 8.

Hz), 7.52 - 7.63 (5H, m), 7.72 (1H, d, J - 2.2 Hz), 7.88 (1H, s) .
IR (KBr) v: 2959, 2934, 2872, 1671, 1590, 1501, 1491 cml.
Anal. Calcd. for C31H36N2~6S: C, 65.94; H, 6.43; N, 4.96.
Found C, 65.82; H, 6.46; N, 4.85.
Reference Example 144 In dichloromethane (20m1) was dissolved methyl 7-bromo-1-phenyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (1g). Under ice-cooling, to the solution was added dropwise chlorosulfonic acid (0.93m1). The mixture was stirred at room temperature for 1 hour, and the reaction solution was added dropwise to 40o methylamine solution in water (25m1) under ice-cooling. The mixture was stirred at room temperature overnight, concentrated and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated to give methyl 7-bromo-1-(N-methyl-4-sulfamoylphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (1g) as yellow crystals.
mp 201 - 204C.

1H-NMR (8 ppm, CDC13) 2. 65 (3H, d, J 5. Hz) , 2. 90 (2H, = 4 t, J = 4.6 Hz), 3.79 (3H, s), 3.84 (2H, t, J = 4.6 Hz), 4.23 ( 1H, q, J = 5 . 4 Hz ) , 6 . 88 ( J 9 Hz ) , 7 . 30 2H, d, = . ( 1H, d, J = 8.8 Hz), 7.44 (1H, dd, J = 2.2, 8.8 Hz), 7.57 - 7.69 ( 4H, m) .
IR (KBr) v: 3277, 2953, 1705, 1595, 1501 cml.
Anal. Calcd. for C19H19BrN209S: C, 50.56 H, 4.24 N, 6.21.
Found C, 50.62; H, 4.20; N, 6.48.
Reference Example 145 A mixture of methyl 7-bromo-1-(N-methyl-4-sulfamoylphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (1g), 4-(2-butoxyethoxy)phenyl borate (0.69g), 1M potassium carbonate solution (8m1), ethanol (8m1) and toluene (100m1) was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakis(triphenylphosphine)palladium (0.13g), and the mixture was refluxed under argon atmosphere for 2.5 hours and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified with silica gel column chromatography (ethyl DEMANDES OU BREVETS VOLUMINEUX
LA PRESENTE PARTIE DE CETTE DEMANDE OU CE BREVETS
COMPREND PLI1S D'UN TOME.

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Claims (37)

WHAT IS CLAIMED IS:

1. A compound of the formula (I):
wherein R1 is a 5- to 6-membered aromatic ring which has a group of the formula: R-Z1-X-Z2- wherein R is a hydrogen atom or an optionally substituted hydrocarbon group, X is an optionally substituted alkylene chain, and Z1 and Z2 are respectively hetero-atoms, and which may have a further substituent, the group R may bind to the 5- to 6-membered aromatic ring to form a ring, Y is an optionally substituted imino group, R2 and R3 are respectively an optionally substituted aliphatic hydrocarbon group or an optionally substituted alicyclic heterocyclic group; or a salt thereof.

2. A pro-drug of the compound according to claim 1 or a salt thereof.

3. The compound according to claim 1, wherein the 5-to 6-membered aromatic ring is benzene, furan or thiophene.

4. The compound according to claim 1, wherein the 5-to 6-membered aromatic ring is benzene;

5. The compound according to claim 1, wherein R is an optionally halogenated lower alkyl group.

6. The compound according to claim 1, wherein X is -(CH2)n- (n is an integer of 1-4).

7. The compound according to claim 1, wherein Z1 and Z2 are respectively -O-, -S(O) m- (m is an integer of 0-2) or -N(R4)- (R4 is a hydrogen atom or an optionally substituted lower alkyl group).

8. The compound according to claim 1, wherein Z1 is -O- or -S(O) m- (m is an integer of 0-2).

9. The compound according to claim 1, wherein Z1 is -O-.

10. The compound according to claim 1, wherein Z2 is -O- or -N(R4)- (R4 is a hydrogen atom or an optionally substituted lower alkyl group).

11. The compound according to claim 1, wherein Z2 is -O-.

12. The compound according to claim 1, wherein Y is -N(R5)- (R5 is a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted acyl group).

13. The compound according to claim 12, wherein (R5) is C1-4 alkyl, formyl or C2-5 alkanoyl.

14. The compound according to claim 12, wherein R5 is a group represented by the formula -(CH2)k-R6: wherein k is 0 or 1, and R6 is an optionally substituted 5- to 6-membered monocyclic aromatic group.

15. The compound according to claim 1, wherein R2 is an optionally substituted straight chain hydrocarbon group.

16. The compound according to claim 1, wherein R2 is an optionally substituted lower alkyl group.

17. The compound according to claim 1, wherein R3 is an optionally substituted alicyclic hydrocarbon group or an optionally substituted alicyclic heterocyclic group.

18. The compound according to claim 17, wherein the alicyclic hydrocarbon group is a lower cycloalkyl group.

19. The compound according to claim 17, wherein the alicyclic hydrocarbon group is cyclohexyl.

20. The compound according to claim 17, wherein the alicyclic heterocyclic group is a saturated alicyclic heterocyclic group.

21. The compound according to claim 17, wherein the alicyclic heterocyclic group is tetrahydropyranyl, tetrahydrothiopyranyl or piperidyl.

22. The compound according to claim 17, wherein the alicyclic heterocyclic group is tetrahydropyranyl.

23. A compound selected from the class consisting of 7-(4-ethoxyethoxephenyl)-1-ethyl-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carbiboxamide, 1-ethyl-7-(4-propoxyethoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide, 7-(4-butoxyethoxyphenyl)-1-ethyl-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide, 7-(4-ethoxyethoxyphenyl)-1-formyl-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide, 1-formyl-7-(4-propoxyethoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide, 7-(4-butoxyethoxyphenyl)-1-formyl-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide, 7-(4-butoxyethoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-5-yl)amino]methyl]phenyl]-1-propyl-2,3-dihydro-1-benzazepine-4-carboxamide, N-[4-[[N-methyl-N-(tetrahydropyran-5-yl)amino]methyl]phenyl]-7-(4-propoxyethoxyphenyl)-1-propyl-2,3-dihydro-1-benzazepine-4-carboxamide, 1-benzyl-7-(4-butoxyethoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide, 7-(4-butoxyethoxyphenyl)-1-cyclopropylmethyl-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide, 7-(4-butoxyethoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1-phenyl-2,3-dihydro-1-benzazepine-4-carboxamide, 7-(4-butoxyethoxyphenyl)-1-(3,4-methylenedioxy)phenyl-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide, 7-(4-butoxyethoxyphenyl)-1-(2-methyloxazol-5-yl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide, 1-allyl-7-(4-butoxyethoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide, 7-(4-butoxyethoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1-(3-thienyl)methyl-2,3-dihydro-1-benzazepine-4-carboxamide, 7-(4-butoxyethoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1-(thiazol-2-yl)methyl-2,3-dihydro-1-benzazepine-4-carboxamide, 7-(4-butoxyethoxyphenyl)-1-(1-methylpyrazol-4-yl)methyl-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide, 7-(4-butoxyethoxyphenyl)-1-(3-methylisothiazol-4-yl)methyl-N-[4-[[N-methyl-N-(tetrahydropyran-5-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide, 7-(4-butoxyethoxyphenyl)-1-(1-ethylpyrazol-4-yl)methyl-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide, 7-(4-butoxyethoxyphenyl)-1-isobutyl-N-[4-[[N-methyl-N-(tetrahydropyran-5-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide, 1-isobutyl-N-[4-[[N-methyl-N-(tetrahydropyran-5-yl)amino]methyl]phenyl]-7-(4-propoxyethoxyphenyl)-2,3-dihydro-1-benzazepine-4-carboxamide, 7-(4-butoxyethoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1-(thiazol-5-yl)methyl-2,3-dihydro-1-benzazepine-4-carboxamide, 7-(4-butoxyethoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1-(1-methyltetrazol-5-yl)methyl-2,3-dihydro-1-benzazepine-4-carboxamide, and 7-(4-butoxyethoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1-(2-methyltetrazol-5-yl)methyl-2,3-dihydro-1-benzazepine-4-carboxamide, or salt thereof.

24. A pro-drug of the compound according to claim 23 or a salt thereof.

25. A method for producing a compound of the formula:

wherein each symbol is as defined in claim 1, or a salt thereof, which comprises subjecting a compound of the formula:
wherein each symbol is as defined in claim 1, a salt or a reactive derivative thereof to a condensation reaction with a compound of the formula:
wherein each symbol is as defined in claim 1, or a salt thereof.

26. A pharmaceutical composition which comprises the compound according to claim 1 or a salt thereof.

27. The composition according to claim 26, which is a CC chemokine receptor antagonist.

28. The pharmaceutical composition according to claim 26, which is a CCR5 antagonist.

29. The composition according to claim 26, which is for the treatment or prevention of infectious disease of HIV.

30. The composition according to claim 26, which is for the treatment or prevention of AIDS.

31. The composition according to claim 26, which is for the prevention of the progression of AIDS.

32. The composition according to claim 29, which is used in combination with a protease inhibitor and/or a reverse transcriptase inhibitor.

33. The composition according to claim 32, wherein the reverse transcriptase inhibitor is zidovudine, didanosine, zalcitabine, lamivudine, stavudine, nevirapine, delavirdine, efavirenz or abacavir.

34. The composition according to claim 32, wherein the protease inhibitor is saquinavir, ritonavir, indinavir or nelfinavir.

35. Use of the compound according to claim 1 or a salt thereof in combination with a protease inhibitor and/or a reverse transcriptase inhibitor for the treatment or prebention of infectious disease of HIV.

36. A method for antagonizing a CC chemokine receptor in a mammal, which comprises administering an effective amount of a compound according to claim 1 or a salt thereof to a mammal.

37. Use of a compound according to claim 1 or a salt thereof in preparation of a medicament for antagonizing a CC chemokine receptor.